Roles of the Altitude-Adapted Immune Microenvironment in Pulmonary Vascular Remodeling in High-Altitude Pulmonary Hypertension: A Review

Introduction

High-altitude pulmonary hypertension (HAPH) is a distinct subtype of pulmonary hypertension characterized by elevated pulmonary arterial pressure secondary to chronic hypobaric hypoxia [1]. Unlike pulmonary arterial hypertension (PAH) occurring at sea level, HAPH is a unique pathophysiological entity arising from long-term residence in low-oxygen environments such as the Qinghai-Tibet altitude, the Andes, and the Ethiopian Highlands. While pulmonary vascular remodeling has long been recognized as the structural basis of increased pulmonary vascular resistance in HAPH, the mechanistic underpinnings of this remodeling remain incompletely understood.

Over the past decade, significant attention has been devoted to the roles of hypoxia-inducible factors (HIFs), endothelin-1, and oxidative stress in driving vascular cell proliferation and endothelial dysfunction [2–6]. However, emerging evidence suggests that hypoxia does not act in isolation. Instead, it orchestrates a complex interplay between vascular cells and immune components, giving rise to a specialized inflammatory and immunoregulatory milieu within the pulmonary circulation [7–9]. This altitude-dependent immune microenvironment, shaped by both sustained hypoxic stress and host genetic adaptation, may serve as a critical modulator of pulmonary vascular remodeling.

Recent single-cell transcriptomic and spatial profiling studies have uncovered dynamic shifts in immune cell composition and function in the lungs of high-altitude residents [10]. These changes include the polarization of alveolar macrophages, hyperactivation of neutrophils with excessive NETosis, and an imbalance between regulatory T cells (Tregs) and Th17 cells, all of which potentially contribute to endothelial injury, smooth muscle proliferation, and (ECM) deposition [11–14]. Moreover, hypoxia-induced metabolic reprogramming in immune cells – particularly the shift towards glycolysis and mitochondrial dysfunction – amplifies inflammatory signaling and can promote a persistent pro-remodeling phenotype [15,16]. Despite these advances, the crosstalk between immune cells and vascular structural cells in the context of HAPH remains largely unexplored. There is a pressing need to delineate how the altitude-adapted immune system influences the initiation and progression of pulmonary vascular remodeling, and whether this axis can be therapeutically targeted.

In this review, we systematically examine the current understanding of the immune landscape in HAPH, with a focus on altitude-dependent immune alterations and their mechanistic contributions to pulmonary vascular remodeling. We highlight key immune cell populations and inflammatory mediators implicated in this process, explore novel immuno-metabolic pathways involved, and discuss emerging immunotherapeutic strategies that may hold promise for the treatment of HAPH. A critical question we aim to contextualize through this analysis is: Could immune-targeted therapies alter the natural history of HAPH in genetically adapted populations? This article reviews the roles of hypoxia, inflammation, and oxidative stress in vascular remodeling in high-altitude pulmonary hypertension.

Immune Adaptation and Remodeling with Long-Term High-Altitude Exposure

INNATE IMMUNITY: POLARIZATION AND FUNCTIONAL REPROGRAMMING:

The innate immune system is the first line of defense against environmental stressors, and under chronic hypobaric hypoxia, its components undergo profound and specialized reprogramming. Rather than conforming to classical M1/M2 paradigms, monocyte–macrophage lineage cells in the hypoxic lung adopt a non-canonical, hybrid activation state, characterized by the concurrent upregulation of proinflammatory mediators (eg, IL-1β, TNF-α) and tissue-remodeling factors (eg, MMP9, ARG1, TGF-β1) [18]. This dual-functional phenotype fosters a parainflammatory state – a sustained, low-grade immune activation that primes the vascular niche for structural remodeling.

Alveolar macrophages at high altitude exhibit enhanced phagocytic activity, increased glycolytic flux, and a transcriptional profile skewed by hypoxia-inducible factor 1-alpha (HIF-1α) signaling [15,19]. Simultaneously, these cells display resistance to apoptotic clearance, contributing to prolonged immune presence and local cytokine burden. Single-cell RNA sequencing (scRNA-seq) studies further reveal a spectrum of macrophage subpopulations with distinct remodeling signatures, including Mrc1hi Trem2+ lipid-associated macrophages that resemble fibrotic phenotypes in other chronic lung diseases [20,21].

Neutrophils, often overlooked in chronic hypoxic conditions, play an underappreciated yet crucial role. Hypoxia prolongs their lifespan, enhances chemotactic responsiveness, and significantly increases the formation of neutrophil extracellular traps (NETs), a phenomenon tightly regulated by HIF-1α stabilization and reactive oxygen species (ROS) accumulation [22,23]. NETs not only damage pulmonary endothelial integrity but also serve as scaffolds for perivascular fibrosis and thrombosis, linking innate immune effector functions to structural vascular alterations [24].

Dendritic cells (DCs) under hypoxic stress exhibit altered migratory behavior, impaired antigen presentation, and a skewed cytokine milieu favoring tolerance or immune deviation [25–28]. Plasmacytoid DCs (pDCs), in particular, show reduced type I interferon production, undermining antiviral immunity and modulating T cell priming. Moreover, hypoxia-exposed conventional DCs preferentially drive Th17 over Th1 responses, reinforcing the pro-remodeling inflammatory axis [29].

Importantly, innate lymphoid cells (ILCs), especially group 2 ILCs (ILC2s), are emerging as oxygen-sensitive regulators of pulmonary homeostasis [30]. Hypoxia enhances ILC2-derived IL-13 production, which promotes smooth muscle hypertrophy and collagen deposition, thereby bridging innate immunity with vascular remodeling.

Chronic hypoxia does not merely activate innate immune cells but also orchestrates a context-specific reprogramming that blurs the boundaries between immune activation, tissue repair, and pathological remodeling. The plasticity and metabolic adaptation of these cells under hypoxic stress not only sustain inflammatory signaling but actively shape the pulmonary vascular architecture, providing a mechanistic link between the immune microenvironment and HAPH progression. This non-canonical reprogramming of innate immunity – from hybrid macrophage polarization to NET-mediated endothelial injury – lays the foundation for subsequent adaptive immune activation.

ADAPTIVE IMMUNITY: T CELL HOMEOSTATIC IMBALANCE AND FUNCTIONAL PLASTICITY:

Chronic exposure to high-altitude hypoxia orchestrates a profound reconfiguration of adaptive immunity, particularly in the T cell compartment, where homeostatic disequilibrium and lineage plasticity emerge as pivotal contributors to the evolving immune microenvironment. Rather than inducing a uniform immunosuppressed state, hypoxia selectively modulates T cell fate decisions, effector functions, and tissue tropism, shaping an immune landscape permissive to pulmonary vascular remodeling.

Hypoxia skews CD4+ T cell polarization away from regulatory phenotypes and toward proinflammatory subsets. Specifically, Th17 and Th1 lineages are preferentially expanded in response to sustained HIF-1α activation and increased glycolytic metabolism, while FOXP3+ Tregs are numerically and functionally suppressed [31–33]. This imbalance amplifies the secretion of cytokines such as IL-17A, IFN-γ, and GM-CSF, which promote endothelial activation, vascular leakage, and smooth muscle proliferation – hallmarks of HAPH pathogenesis. Mechanistically, hypoxia-induced epigenetic remodeling underlies this T cell plasticity [34]. DNA methylation of the FOXP3 promoter and histone acetylation at RORC and TBX21 loci alter chromatin accessibility in a lineage-specific manner, reinforcing proinflammatory commitment [35, 36]. Furthermore, hypoxia reshapes the T cell receptor (TCR) repertoire diversity through altered thymic selection and peripheral clonal expansion, suggesting a long-term shift in immune surveillance and tolerance thresholds at altitude. CD8+ cytotoxic T lymphocytes (CTLs) also exhibit functional bifurcation under hypoxia. While some subsets display impaired cytolytic capacity due to metabolic exhaustion and upregulation of immune checkpoint molecules (eg, PD-1, LAG-3), others adopt tissue-resident phenotypes that persist in the pulmonary interstitium and secrete IFN-γ and granzyme B, potentially aggravating vascular injury [37,38]. In parallel, unconventional T cells, such as γδ T cells and mucosal-associated invariant T (MAIT) cells, are increasingly recognized for their hypoxia-sensitive roles [39,40]. These cells rapidly respond to altered metabolic cues and microbial dysbiosis in the hypoxic lung, producing IL-17, IL-22, and other effector molecules that orchestrate local inflammation, epithelial permeability, and stromal remodeling [37]. Notably, the pulmonary accumulation of tertiary lymphoid structures (TLS) – ectopic lymphoid aggregates enriched in T and B cells – has been observed in chronically hypoxic lungs [41]. These niches not only perpetuate local antigen presentation but also sustain spatially confined proinflammatory loops that interface with vascular structures, providing a potential link between adaptive immunity and perivascular remodeling [42].

In summary, high-altitude hypoxia does not merely impair adaptive immunity but actively reprograms T cell phenotypes, functions, and spatial localization. The resulting functional repolarization and regulatory breakdown foster a maladaptive immune tone that facilitates pulmonary vascular transformation. This adaptive immune imbalance is tightly regulated by metabolic shifts in immune cells, the core mechanisms of which are explored in the next section.

IMMUNE METABOLIC REPROGRAMMING: CENTRAL REGULATORY AXIS:

At high altitude, chronic hypobaric hypoxia not only alters oxygen sensing but also fundamentally rewires the metabolic architecture of immune cells, constituting a central regulatory axis that integrates environmental stress with immune functionality [43]. This hypoxia-driven immunometabolic reprogramming plays a decisive role in the emergence of a persistent, maladaptive immune microenvironment that underpins pulmonary vascular remodeling in HAPH. A hallmark of this metabolic shift is the preferential induction of aerobic glycolysis – a Warburg-like effect – even under oxygen-replete conditions. Innate and adaptive immune cells, particularly macrophages and activated T cells, upregulate glycolytic flux via HIF-1α stabilization (a process that also shapes the transcriptional phenotype of alveolar macrophages, enabling rapid ATP generation and biosynthetic support for effector functions [44,45]. This glycolytic reprogramming not only sustains the production of proinflammatory cytokines (eg, IL-1β, TNF-α, IFN-γ) but also generates metabolic by-products such as lactate, succinate, and itaconate, which act as immunoregulatory signaling molecules [45–47]. Succinate accumulation inhibits prolyl hydroxylases, further stabilizing HIF-1α in a feed-forward loop that amplifies inflammation and promotes transcriptional programs linked to angiogenesis and matrix remodeling [48,49]. Concurrently, lactate export via MCT4 acidifies the extracellular space, leading to endothelial dysfunction, pericyte detachment, and (ECM) degradation [50], all contributing to vascular remodeling.

Moreover, the mitochondrial dysfunction observed in hypoxia-exposed macrophages and T cells is accompanied by increased mitochondrial ROS (mtROS) production, which activates the NLRP3 inflammasome and triggers pyroptotic cell death [51–54]. These events release damage-associated molecular patterns (DAMPs), reinforcing local immune activation and endothelial injury [55–58]. Simultaneously, impaired oxidative phosphorylation limits Treg differentiation and promotes proinflammatory Th17 polarization, establishing a metabolically enforced immune imbalance [59].

Emerging evidence also implicates lipid metabolism in shaping immune phenotypes under hypoxia. Dysregulated fatty acid oxidation (FAO) in alveolar macrophages and DCs impairs their tolerogenic capacity and antigen presentation, while elevated lipid uptake drives foam cell-like transformation, contributing to vascular inflammation and fibrosis [60–62]. Importantly, these metabolic alterations are not merely bystanders but functional orchestrators of the hypoxia-induced immune phenotype. Metabolites act as epigenetic cofactors (eg, α-ketoglutarate and acetyl-CoA), modifying chromatin accessibility and thus reinforcing long-term transcriptional reprogramming [63,64]. This positions immunometabolism as both a sensor and effector of the high-altitude immune response.

In summary, immune metabolic reprogramming under hypoxia is a dynamic, multi-layered process that couples environmental signals to immune fate and function. By shaping cytokine output, effector differentiation, cell death pathways, and epigenetic landscapes, it serves as a central modulator of the immune microenvironment and an upstream driver of pulmonary vascular remodeling in HAPH. While metabolic reprogramming defines immune cell function, the spatial organization of these metabolically altered immune cells further amplifies their pro-remodeling effects, as discussed in the next section.

SPATIAL REORGANIZATION OF THE IMMUNE NICHE AT HIGH ALTITUDE:

Beyond cellular reprogramming, chronic hypobaric hypoxia imposes profound spatial reorganization of the pulmonary immune microenvironment, creating anatomically distinct niches that foster persistent low-grade inflammation and vascular remodeling. Spatial transcriptomics and high-dimensional imaging have revealed that immune cells under hypoxic stress do not distribute randomly but instead form perivascular clusters and tertiary lymphoid-like structures – collectively termed “immune-vascular units” (iVUs) – in proximity to small pulmonary vessels [11,65]. These iVUs are enriched in MHC-II+ macrophages, Th17-polarized CD4+ T cells, and activated dendritic cell subsets, which together orchestrate localized cytokine release (eg, IL-6, IL-17, GM-CSF) and matrix remodeling enzyme production (eg, MMP12, cathepsins) [66,67]. Notably, the accumulation of neutrophils and NETs within these structures exacerbates endothelial injury and fibrin scaffold deposition, setting the stage for fibroblast recruitment and adventitial thickening [68,69]. Moreover, hypoxia-induced chemokine gradients (eg, CXCL12, CCL20) contribute to the topographic sequestration of immune populations within perivascular and peribronchial regions [70–72]. This microanatomical compartmentalization facilitates sustained paracrine signaling loops between immune and structural cells, bypassing systemic regulatory mechanisms and promoting site-specific vascular pathology. Evidence from high-altitude animal models demonstrates that disrupting CXCL12-CXCR4 axis attenuates iVU formation and ameliorates vascular thickening, highlighting its potential as a spatially defined therapeutic target [71,73]. In this context, spatial reorganization is more than a passive byproduct of inflammation – it constitutes a hypoxia-adapted immunoarchitectural strategy that enables localized immune surveillance, effector retention, and structural remodeling. This paradigm shift underscores the need to interpret HAPH not only through the lens of cellular activation but also through the emergent spatial logic of immune-stromal organization within the hypoxic lung. These spatially defined iVUs create the microenvironment necessary for bidirectional crosstalk between immune and structural cells.

HYPOXIA-INDUCED CROSSTALK BETWEEN IMMUNE AND STRUCTURAL CELLS:

Chronic hypoxia at high altitude fundamentally reshapes intercellular communication networks within the pulmonary microenvironment. Central to this remodeling process is the dynamic crosstalk between immune cells and structural cells – namely, pulmonary artery endothelial cells (PAECs), smooth muscle cells, fibroblasts, and pericytes. This bidirectional interaction underpins the transition from transient inflammation to chronic vascular remodeling, a hallmark of HAPH.

Under sustained hypoxia, immune cells acquire a tissue-resident phenotype characterized by prolonged retention and enhanced effector functions [74,75]. These cells, particularly alternatively activated macrophages and Th17-skewed T cells, secrete a repertoire of cytokines (eg, IL-1β, IL-6, TNF-α), growth factors (eg, TGF-β1, PDGF-BB), and proteolytic enzymes (eg, MMP9), which directly modulate the phenotype and behavior of structural cells [76,77]. For instance, IL-6 signaling promotes PASMC proliferation via STAT3 activation, while macrophage-derived TGF-β1 induces endothelial-to-mesenchymal transition (EndMT), contributing to intimal fibrosis and loss of vascular compliance [78,79]. Conversely, structural cells under hypoxic stress are not passive recipients but active participants in immune modulation. PAECs upregulate adhesion molecules (eg, ICAM-1, VCAM-1) and chemokines (eg, CCL2, CX3CL1), which promote immune cell adhesion, transmigration, and perivascular accumulation [80,81]. Hypoxic fibroblasts secrete (ECM) components and alarmins (eg, HMGB1, S100A8/A9), further amplifying local immune activation and sustaining a feed-forward loop of inflammation and remodeling [82,83].

Recent single-cell and spatial transcriptomic data suggest the existence of transitional cell states – such as inflammatory fibroblasts and mesenchymal-like endothelial cells – that act as cellular intermediates in this crosstalk [84]. These populations exhibit dual immunomodulatory and structural remodeling functions, making them potential keystone players in hypoxia-induced vascular pathology. The spatiotemporal orchestration of this immune-structural dialogue is tightly regulated by HIFs, particularly HIF-1α and HIF-2α, which serve as transcriptional integrators across cell types [85,86]. The convergence of HIF-driven signaling in both immune and structural compartments amplifies the pathological remodeling cascade, establishing a maladaptive immune microenvironment that perpetuates pulmonary hypertension [87].

Understanding this multicellular, hypoxia-synchronized crosstalk offers novel insights into the immunopathogenesis of HAPH and points toward therapeutic strategies that target intercellular communication hubs – such as HIF signaling nodes, cytokine-receptor axes, and extracellular matrix-immune interfaces – rather than individual cell types alone (Figure 1).

To summarize, chronic high-altitude hypoxia induces non-canonical reprogramming of both innate and adaptive immunity, coupled with immune metabolic shifts and spatial reorganization of iVUs. These integrated immune adaptations, while initially protective, drive pathogenic crosstalk with vascular structural cells, laying the foundation for the immune–vascular remodeling mechanisms detailed below.

Immuno-Vascular Interactions in High-Altitude Pulmonary Vascular Remodeling: Mechanisms of Microenvironmental Orchestration

INFLAMMATORY SIGNALING LOOPS AND ENDOTHELIAL DYSFUNCTION:

Chronic hypobaric hypoxia at high altitude acts as a persistent trigger for immune activation, establishing a self-perpetuating inflammatory milieu that profoundly alters pulmonary endothelial cell homeostasis. Accumulating evidence indicates that this low-grade, yet sustained, inflammation is not a mere bystander but an active contributor to vascular pathology through the formation of inflammatory signaling loops, wherein immune and endothelial cells engage in reciprocal activation. One of the key hallmarks of this interaction is the persistent upregulation of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, secreted predominantly by activated macrophages and Th1/Th17 cells [88–90]. These mediators activate endothelial NF-κB and STAT3 signaling pathways, leading to transcriptional reprogramming that enhances EC permeability, promotes leukocyte adhesion (via ICAM-1/VCAM-1), and initiates oxidative stress cascades [91]. In parallel, HIF-1α – whose role in immune cell polarization and metabolic reprogramming is detailed in Sections 2.1 and 2.3 – synergizes with inflammatory transcription factors, amplifying cytokine responsiveness and exacerbating the inflammatory feedback loop [92]. Furthermore, NETs – abundantly formed under hypoxic and inflammatory stimuli – have emerged as critical effectors in mediating endothelial pyroptosis, primarily through the release of histones, proteases, and ROS [93,94]. This process contributes to endothelial injury and further escalates immune activation by exposing DAMPs into the microenvironment (Figure 2).

Recent findings also underscore the role of CD8+ T cells and NK cells in driving endothelial exhaustion, characterized by the upregulation of checkpoint molecules (PD-L1, TIM-3) and metabolic impairment [95,96]. These cytotoxic lymphocytes, often residing in the perivascular space, induce sublethal stress and apoptosis in ECs, undermining vascular barrier integrity [97]. Importantly, endothelial dysfunction under chronic hypoxic inflammation is not limited to increased permeability or cell death; it also involves phenotypic switching toward a mesenchymal-like state, a process known as EndMT [98]. Inflammatory mediators, notably TGF-β1, IL-6, and Notch ligands, synergize with hypoxia to induce EndMT, marked by the loss of endothelial markers (eg, CD31, VE-cadherin) and gain of mesenchymal traits (eg, α-SMA, vimentin) [99]. This transition directly contributes to perivascular fibrosis and intimal thickening.

Collectively, the high-altitude immune microenvironment fosters a feed-forward loop in which inflammation and endothelial dysfunction reinforce each other, serving as a critical initiating step in hypoxia-induced pulmonary vascular remodeling. Understanding and targeting the nodes of this loop may open avenues for early intervention in HAPH.

IMMUNE-MEDIATED SMOOTH MUSCLE CELL PROLIFERATION AND PHENOTYPIC SWITCHING:

Under chronic high-altitude hypoxia, pulmonary artery PASMCs undergo marked phenotypic plasticity, transitioning from a quiescent, contractile phenotype to a synthetic, proliferative state that contributes to vascular thickening and lumen narrowing. Recent evidence implicates the altitude-dependent immune microenvironment as a pivotal extrinsic regulator of this phenotypic switch.

Proinflammatory cytokines secreted by infiltrating immune cells – particularly IL-6, IL-1β, TNF-α, and GM-CSF – activate downstream JAK/STAT3, NF-κB, and MAPK signaling cascades within PASMCs, promoting cell cycle entry, mitochondrial biogenesis, and increased protein synthesis [100,101]. Hypoxia-conditioned macrophages (especially CD206+ ARG1+ alternatively activated subsets) release osteopontin (SPP1) and PDGF-BB, which synergistically drive PASMC dedifferentiation and clonal expansion [102,103]. This immune-derived trophic support is spatially enriched in the perivascular niche, where immune cells form intimate contact zones with PASMCs through the CX3CL1-CX3CR1 and ICAM-1–LFA-1 axes. In parallel, hypoxia-induced metabolic rewiring of both immune and vascular cells (characterized by HIF-1α-driven aerobic glycolysis and lactate accumulation) establishes a lactate-rich, acidic microenvironment. This condition favors histone deacetylase (HDAC)-mediated chromatin remodeling in PASMCs, suppressing contractile markers such as MYH11 and ACTA2, while upregulating proliferation-associated genes like PCNA and cyclin D1 [104]. These changes are further reinforced by immune-derived extracellular vesicles (EVs) containing miR-221/222, which directly target transcriptional repressors of proliferation.

An emerging paradigm suggests that this immune–smooth muscle crosstalk is not merely paracrine but is also reciprocal. PASMCs under phenotypic switching secrete CCL2 and IL-33, which promote macrophage recruitment and Th2 cell polarization, thereby perpetuating a feed-forward remodeling loop [105]. This bidirectional dialogue exemplifies how immune-driven niche dynamics orchestrate vascular structural plasticity in HAPH. Targeting these immune-instructed transitions – either by modulating macrophage-derived growth factors or disrupting EV-mediated epigenetic reprogramming – may be novel strategies to halt or reverse vascular remodeling in HAPH.

FIBROBLAST ACTIVATION AND ADVENTITIAL REMODELING DRIVEN BY IMMUNE CUES:

The adventitia, long regarded as a passive structural compartment of the pulmonary vasculature, has emerged as an immunologically active niche critically involved in the pathogenesis of HAPH. Under chronic hypoxic exposure, immune cell accumulation within the adventitia initiates a cascade of signaling events that reprogram resident fibroblasts into activated myofibroblast-like cells, contributing to maladaptive extracellular matrix (ECM) remodeling, vascular stiffening, and perivascular fibrosis.

Fibroblast activation in this context is primarily orchestrated by immune-derived soluble factors. Proinflammatory cytokines such as IL-1β, IL-6, and TNF-α, secreted by adventitial macrophages and Th17 cells, induce the expression of α-smooth muscle actin (α-SMA), fibronectin, and collagen I in pulmonary adventitial fibroblasts [106]. Additionally, sustained TGF-β1 signaling, potentiated by hypoxia-induced HIF-1α stabilization, synergizes with IL-13 and IL-17A to reinforce fibroblast-to-myofibroblast transition [107]. This phenotypic conversion is not merely a byproduct of inflammation, but is a directed process that contributes to matrix stiffening and the formation of fibrotic foci surrounding small pulmonary vessels (Figure 3).

Beyond soluble mediators, cell–cell and cell–matrix interactions play a vital role. Fibroblasts express pattern recognition receptors such as TLR4 and NOD2, rendering them responsive to DAMPs released from hypoxic endothelial and PASMCs [108]. These signals, amplified in the presence of infiltrating NETs, further stimulate fibroblast proliferation and matrix deposition. In this pro-fibrotic milieu, fibroblasts also acquire immunomodulatory functions, secreting CCL2 and CXCL12 to recruit monocytes and T cells, thereby sustaining a chronic inflammatory circuit [109]. Importantly, recent spatial transcriptomics and single-cell analyses of hypoxic lung tissue have identified a unique subset of adventitial fibroblasts expressing periostin (POSTN), tenascin-C (TNC), and PDPN, enriched specifically in perivascular fibrotic zones [110]. These immune-sensing fibroblasts display epigenetic priming, including H3K4me1 enrichment at pro-fibrotic loci, suggesting a form of trained immunity or innate memory that can perpetuate remodeling even after the initial hypoxic insult is resolved.

Collectively, these findings position the adventitia as a dynamic immuno-fibrotic interface wherein immune-fibroblast crosstalk drives structural remodeling. Targeting immune-primed fibroblast subpopulations, or their metabolic and epigenetic programming, may be a novel therapeutic axis to attenuate or reverse vascular fibrosis in HAPH.

IMMUNE–ENDOTHELIAL–MESENCHYMAL TRANSITION AXIS:

EndMT is a pivotal mechanism of vascular remodeling, wherein endothelial cells lose their canonical markers (eg, CD31, VE-cadherin) and acquire mesenchymal features such as α-smooth muscle actin (α-SMA), vimentin, and fibronectin [111]. In the setting of HAPH, chronic hypobaric hypoxia triggers a complex immune-mediated milieu that accelerates and sustains EndMT, contributing to neointimal formation, medial thickening, and perivascular fibrosis [112].

Recent evidence suggests that the immune microenvironment is not merely permissive but actively instructive in promoting EndMT. Proinflammatory cytokines such as IL-1β, TNF-α, and IL-6, released by activated macrophages and Th17 cells, act synergistically with HIF-1α to activate key EndMT-inducing transcription factors, including Snail, Slug, Twist1, and Zeb1 [113]. Concurrently, TGF-β1 – abundantly produced by Tregs and alternatively activated macrophages under hypoxia – acts as a central driver of the SMAD2/3 and non-SMAD signaling cascades that enforce mesenchymal reprogramming in ECs [112]. Beyond canonical cytokine signaling, emerging data highlight the role of EVs derived from immune cells as carriers of EndMT-modulating cargo. Hypoxia-conditioned macrophages and T cells release EVs enriched in miR-21, miR-155, and lncRNA MALAT1, which suppress endothelial-specific gene expression and enhance mesenchymal differentiation [114]. Notably, immune cell-derived EVs also contain mitochondrial DNA and proinflammatory lipids that engage pattern recognition receptors in ECs, fueling a type I interferon response and oxidative stress that further promote EndMT [115].

A novel dimension of this axis involves the metabolic rewiring of ECs under immune influence. Exposure to IFN-γ and IL-6 shifts EC metabolism toward glycolysis and disrupts mitochondrial integrity, a process that not only compromises endothelial barrier function but also sensitizes ECs to EndMT induction [116]. Metabolic intermediates such as succinate and lactate, secreted by neighboring immune or structural cells, may act in a paracrine fashion to stabilize HIFs and activate pro-EndMT pathways [117]. Furthermore, spatial transcriptomic analyses of hypoxic lung vasculature reveal clusters of ECs undergoing partial or hybrid EndMT – cells co-expressing endothelial and mesenchymal markers – localized at the interface of immune infiltrates and remodeled vessels. These transitional phenotypes can act as progenitors for pathological vascular cell lineages and contribute to persistent remodeling even after normoxic restoration [118].

In sum, the immune–EndMT axis in HAPH epitomizes the interplay between inflammation, hypoxia, and vascular plasticity. Dissecting the temporal and spatial dynamics of immune-mediated EndMT, and identifying tractable molecular checkpoints within this axis, may unveil promising therapeutic targets for halting or reversing vascular remodeling in hypoxia-driven pulmonary hypertension.

TEMPORAL AND SPATIAL DYNAMICS OF THE REMODELING-DRIVING IMMUNE MICROENVIRONMENT:

Pulmonary vascular remodeling in HAPH is not a static process but evolves through temporally and spatially orchestrated immune events. Dissecting the spatiotemporal architecture of the immune microenvironment reveals the chronological hierarchy of inflammatory and reparative signals and the anatomical niches where pathogenic immune–vascular crosstalk is most prominent. This dynamic remodeling landscape is shaped by the progressive infiltration, activation, and redistribution of immune cells under chronic hypoxic stress.

Temporally, the immune response transitions from an acute, predominantly innate phase to a chronic, adaptive-driven phase, each characterized by distinct molecular mediators and remodeling phenotypes. In the early hypoxic phase, DAMPs and hypoxia-induced alarmins trigger a rapid influx of neutrophils and proinflammatory macrophages, which secrete matrix metalloproteinases (MMPs), ROS, and cytokines such as IL-1β and TNF-α. These factors initiate endothelial injury, increase vascular permeability, and prime the microenvironment for EndMT and smooth muscle cell activation [119]. As hypoxia persists, monocyte-derived macrophages undergo M1-to-M2 polarization, while DCs and effector T cells – particularly Th17 and cytotoxic CD8+ subsets – populate the perivascular space, amplifying chronic inflammation and sustaining structural remodeling [11].

Spatially, immune cell distribution is nonuniform and region-specific. Perivascular immune aggregates, particularly in small pulmonary arteries, serve as microanatomical hubs of remodeling, where dense accumulations of macrophages, T cells, and fibroblasts form tertiary-like lymphoid structures (TLSs). These structures create localized cytokine-rich milieus that perpetuate SMC proliferation, fibroblast activation, and ECM deposition. Intravascular compartments display endothelial cell subsets undergoing inflammatory activation or EndMT, often in direct contact with patrolling monocytes and platelet–leukocyte aggregates, which further disrupt endothelial integrity [120].

Advanced spatial omics technologies have enabled the identification of functional immune niches characterized by specific cellular architectures and signaling gradients. For example, regions of high HIF-1α activity coincide with perivascular immune clusters expressing IL-6, TGF-β, and IFN-γ, suggesting hypoxia-induced zonation of immune-driven remodeling [10]. Time-resolved single-cell RNA-seq studies reveal that distinct immune subpopulations exhibit phase-specific transcriptional reprogramming [121] – such as early neutrophil oxidative signatures versus late-stage macrophage fibrotic programs – highlighting the necessity of temporal precision in therapeutic intervention. Importantly, the interplay between spatial organization and temporal activation determines the reversibility or irreversibility of vascular remodeling. While early immune-mediated changes may be resolved upon normoxic recovery, chronic perivascular immune niches establish a fibrotic and pro-proliferative microenvironment that resists regression. This underscores the potential of spatiotemporally targeted immunomodulation – such as inhibition of localized TLS formation or stage-specific blockade of cytokine axes – as a novel therapeutic strategy in HAPH.

The immune microenvironment in HAPH is not merely a background factor but is a temporally and spatially active driver of vascular pathology. Future studies integrating longitudinal spatial transcriptomics, 3D immune mapping, and fate-tracing models are essential to decode the precise immuno-architectural dynamics that dictate pulmonary vascular fate under chronic hypoxia.

The mechanistic links between the altitude-adapted immune microenvironment and pulmonary vascular remodeling include inflammatory signaling loops driving endothelial dysfunction and pyroptosis, immune cytokines inducing PASMC phenotypic switching, immune cues activating adventitial fibroblasts, and EndMT acting as a key bridge between endothelial injury and fibrosis. These processes are further shaped by the temporal and spatial dynamics of immune activation, providing a mechanistic framework for the translational therapeutic strategies discussed below.

Translational Potential of Targeting Immune-Mediated Pathways in HAPH Therapy

The pathophysiology of HAPH hinges on the intricate interplay between immune cell activation, metabolic reprogramming, and vascular remodeling. Given the pivotal role of the immune microenvironment in driving pulmonary vascular alterations, targeting immune-mediated pathways offers a promising therapeutic avenue for HAPH management. However, therapeutic strategies must navigate the complex, multi-layered immune responses to avoid broad immunosuppression and focus on precise modulation of key immune signaling events driving vascular remodeling.

A promising strategy lies in modulating macrophage polarization. The inflammatory phenotype of macrophages, particularly the M1-like macrophages, exacerbates endothelial dysfunction and promotes smooth muscle cell hyperplasia through the release of proinflammatory cytokines such as TNF-α and IL-1β. Gonzalez demonstrated that enhancing macrophage M2 polarization effectively ameliorates hypoxia-induced pulmonary vascular remodeling in mice with PAH by promoting inflammation resolution [121]. Similarly, Liu et al reported that intravenous administration of exosomes derived from human umbilical cord mesenchymal stromal cells facilitates M2 polarization and improves vascular remodeling in PAH mouse models [122]. These findings show that therapeutic strategies aimed at promoting the alternatively activated, tissue-protective M2 phenotype may limit the progression of HAPH by attenuating vascular inflammation and suppressing PASMC proliferation, without eliciting the broad-spectrum immunosuppression typically associated with conventional corticosteroid therapies.

Beyond macrophages, T cell-mediated immune responses are another critical therapeutic target in the context of hypoxia-induced pulmonary vascular remodeling. Under chronic hypoxic conditions, an imbalance between Th17 and Tregs fosters a proinflammatory milieu that contributes to pulmonary vascular injury. Restoring this immune axis can reduce vascular permeability and mitigate excessive vascular remodeling. Tregs, known for their immunosuppressive properties, can be expanded or transferred to re-establish immune homeostasis and counteract the detrimental effects of hypoxia-induced inflammation. Histone deacetylases (HDACs) are key modulators of Treg functionality. Chen et al demonstrated that the HDAC inhibitor SAHA ameliorates hypoxia-induced pulmonary hypertension in rats by promoting Treg induction and attenuating vascular muscularization and EndMT [123]. Moreover, Li et al found that both resveratrol alone and in combination with the RORγt antagonist SR1001 significantly suppressed hypoxia-induced Th17 differentiation and improved pulmonary vascular remodeling [124]. These insights underscore the potential of developing Th17-specific cytokine inhibitors as a targeted therapeutic strategy to prevent the Th17-driven hyperinflammation that underlies the pathogenesis of HAPH.

The metabolic reprogramming of immune cells under chronic hypoxia also offers a novel therapeutic strategy. The switch to aerobic glycolysis in immune cells and pulmonary vascular PASMCs promotes a hyperproliferative and inflammatory phenotype, which accelerates vascular remodeling. Targeting this metabolic shift with metabolic modulators, such as inhibitors of glycolytic enzymes (eg, hexokinase 2 or lactate dehydrogenase), could attenuate immune cell activation and smooth muscle cell proliferation. Mitochondrial-targeted therapies might further enhance vascular function by restoring normal mitochondrial function in PASMCs and improving endothelial integrity.

Immune–vascular remodeling interactions involving fibroblasts and endothelial cells present additional therapeutic targets. The activation of fibroblasts by immune-derived signals and their subsequent transition into myofibroblasts promotes ECM deposition and adventitial fibrosis, which contribute to pulmonary hypertension. Fibroblast-targeted therapies, such as inhibitors of TGF-β or integrin-mediated signaling, could disrupt these remodeling processes and restore normal vascular architecture. The inhibition of endothelial–mesenchymal transition (EndoMT) is another promising approach, as EndoMT plays a central role in vascular fibrosis and remodeling. By targeting signaling pathways that mediate EndoMT, such as Wnt/β-catenin and Notch pathways, it may be possible to prevent or reverse endothelial dysfunction and prevent excessive adventitial fibrosis.

In conclusion, the therapeutic targeting of immune-driven pathways in HAPH is a novel and promising strategy. A nuanced approach that selectively modulates immune responses while preserving immune homeostasis could provide a more effective treatment modality for HAPH compared to conventional therapies aimed at pulmonary vasodilation alone.

To summarize, there are promising translational strategies targeting the immune-driven pathogenesis of HAPH: modulating macrophage polarization, restoring T cell homeostasis, targeting immune metabolism, and blocking immune-mediated EndMT/fibroblast activation. These strategies prioritize “precision immunomodulation” over broad immunosuppression, aligning with the mechanistic insights into immune–vascular crosstalk, and set the stage for discussing future research gaps.

Future Directions and Challenges in Understanding Immune Microenvironment in HAPH

While significant progress has been made in elucidating the immune mechanisms underlying HAPH, several key questions remain that warrant further investigation. Understanding the precise nature of the immune microenvironment and its dynamic changes over time will be crucial for developing more effective therapies that address not only the vascular remodeling but also the underlying immune dysregulation in HAPH.

One critical area for future research lies in the temporal and spatial dynamics of immune responses. Immune cell activation in HAPH is not a static process; it is intricately linked to the chronic and fluctuating hypoxic conditions at high altitudes. However, the precise timeline of immune cell activation, recruitment, and resolution remains poorly understood. Investigating the longitudinal changes in immune cell subsets, their functional states, and the interplay with structural cells over time could offer novel insights into the onset and progression of vascular remodeling in HAPH. Moreover, utilizing cutting-edge techniques such as single-cell RNA sequencing and spatial transcriptomics will allow for a more granular understanding of how immune cells spatially organize within the lung vasculature and interact with endothelial and PASMCs. These technologies could identify novel molecular signatures or immune cell checkpoints that could serve as therapeutic targets for modulating the immune response in HAPH.

Another exciting avenue for exploration is the role of metabolic reprogramming in the immune microenvironment. It is now well-established that chronic hypoxia induces metabolic shifts in immune cells, similar to the Warburg effect observed in cancer. However, the specific metabolic pathways that drive immune cell activation, immune cell trafficking, and vascular remodeling in HAPH are still not fully elucidated. Future studies should aim to map the metabolic landscapes of immune cells in the HAPH context, specifically focusing on the role of lactate, succinate, and other metabolic intermediates that may influence the inflammatory responses and vascular changes. Identifying metabolic vulnerabilities in immune cells and PASMCs could provide new therapeutic strategies aimed at metabolic reprogramming, which could mitigate both inflammation and fibrosis, thus preventing or reversing vascular remodeling.

Immune–vascular interactions beyond the commonly studied endothelial cells and PASMCs are an emerging area of interest. For instance, the role of fibroblasts and pericytes in the context of immune-mediated vascular remodeling remains underexplored. Recent studies have suggested that immune cells not only stimulate vascular smooth muscle proliferation but also activate fibroblasts, which in turn promote ECM deposition and vascular fibrosis. Delving deeper into the immune-fibroblast axis and how fibroblasts contribute to endothelial dysfunction and adventitial remodeling could uncover novel cellular targets for therapeutic intervention. Additionally, further research is needed to investigate the role of adventitial immune cell infiltration, which is increasingly recognized as a critical component of vascular remodeling in pulmonary hypertension.

A promising but challenging aspect of future research is the development of personalized immunotherapies for HAPH patients. The immune microenvironment in HAPH is highly heterogeneous, and is shaped by genetic, environmental, and individual physiological factors. Thus, a one-size-fits-all approach to immune modulation may not be effective. Personalized therapies, based on individual immune profiles and tailored to the unique immune signature of each patient, are the future of HAPH treatment. Advances in immune profiling using multi-omics approaches and biomarker discovery will be essential in identifying specific immune signatures predictive of response to therapy. Additionally, exploring the therapeutic potential of immune checkpoint inhibitors, cytokine-based therapies, and immune cell modulation could offer individualized treatment options that are more effective and less prone to adverse effects.

In conclusion, while the immune microenvironment plays a central role in the pathogenesis of HAPH, there remains a significant need for further research to understand the molecular, metabolic, and cellular interactions driving vascular remodeling in this context. By addressing the challenges of temporal dynamics, metabolic reprogramming, immune-fibroblast interactions, and personalized therapies, future research will pave the way for more targeted, effective interventions for patients with HAPH.

Discussion

Chronic hypobaric hypoxia, a hallmark of high-altitude exposure, induces a complex immunological adaptation that extends beyond transient inflammation, establishing an altitude-dependent immune microenvironment that actively participates in the orchestration of pulmonary vascular remodeling. This review shows the shift from the classical view of immune cells as passive responders to hypoxic stress toward a paradigm wherein innate and adaptive immune components function as critical architects of vascular structural remodeling in HAPH.

A central axis in this immuno-structural crosstalk is the persistent activation and phenotypic polarization of macrophages and DCs, which not only maintain a proinflammatory milieu via sustained secretion of IL-6, TNF-α, and type I interferons but also modulate endothelial permeability and junctional integrity. These effects are compounded by T cell-driven disturbances in immune homeostasis, particularly the Th17/Treg imbalance, which perpetuates endothelial activation and inflammatory signaling loops, promoting vascular leakage and leukocyte extravasation [18].

Moreover, the immune-driven phenotypic switching of pulmonary artery PASMCs, from a contractile to a synthetic state, is a defining feature of hypoxia-induced vascular remodeling. Immune-derived cytokines such as IL-1β, IFN-γ, and osteopontin reprogram PASMCs to adopt a proliferative, migration-prone phenotype, supporting neointima formation and luminal narrowing. This process is tightly linked to metabolic reprogramming, where immune-mediated stabilization of HIF-1α and activation of glycolytic pathways reinforce a hyperproliferative PASMC phenotype [78,79].

Fibroblast activation and adventitial remodeling, traditionally considered downstream or passive events, are immune-responsive processes. Cytokines and DAMPs released by immune cells drive perivascular fibroblasts into a myofibroblastic state, contributing to ECM remodeling and mechanical stiffening of the vascular wall [120]. This not only exacerbates vascular resistance but also feeds forward into immune cell retention and activation via ECM-immune interactions.

Finally, we summarize both the currently established and the potential future immunomodulatory therapeutic strategies targeting HAPH, while also proposing directions for future research. Overall, immunoregulation is a promising and evolving therapeutic avenue for the treatment of HAPH.

Future Directions

While this review clarifies the role of the altitude-adapted immune microenvironment in HAPH-associated vascular remodeling, key gaps remain: the interplay between host genetic adaptation and immune cell metabolism/immune–vascular crosstalk needs definition, preclinical models require validation with human-derived systems for clinical translation, and the optimal timeline for immune intervention remains unclear. Therapeutically, the mechanistic insights here support prioritizing precision immunomodulation, such as targeting HIF-1α-driven glycolysis or restoring Th17/Treg balance, over broad immunosuppression, with potential synergy when combined with conventional vasodilators to address both remodeling and acute pressure elevation.

Conclusions

The altitude-adapted immune microenvironment, characterized by innate immune reprogramming, adaptive immune imbalance, and immunometabolic shifts under chronic high-altitude hypoxia, serves as a central driver of pulmonary vascular remodeling in HAPH by mediating endothelial dysfunction, pulmonary artery smooth muscle cell proliferation, and adventitial fibrosis. Targeting altitude-adapted immune microenvironment-related pathways, such as promoting M2 macrophage polarization or inhibiting immune-mediated EndMT, offers promising precision therapeutic strategies for HAPH, while further research on spatiotemporal dynamics of altitude-adapted immune microenvironment-vascular crosstalk is essential to translate these insights into clinical practice.

Data Availability

No data were used for the research described in the article.