Pulmonary hypertension (PH) is a progressive and fatal cardiopulmonary disease characterized by sustained elevation of pulmonary artery pressure. The progression of the disease will gradually lead to right heart failure and even death^[1-3]. In clinical diagnosis, a resting mean pulmonary arterial pressure (mPAP) > 20 mmHg measured by right heart catheterization is used as the criterion for diagnosing PH^[4]. According to the differences of etiology and pathogenesis, PH is classified into five types: (1) Pulmonary arterial hypertension (PAH), a group of rare and severe vascular disorders targeting pulmonary arterioles; (2) PH due to left heart disease(PH-LHD), the most common subtype caused by left ventricular or valvular heart diseases; (3) PH caused by pulmonary disease and/or hypoxia, mainly induced by chronic obstructive pulmonary disease, interstitial lung disease or high-altitude hypoxia; (4) Chronic thromboembolic pulmonary hypertension (CTEPH), characterized by unresolved or recurrent pulmonary thromboembolism and subsequent vascular remodeling; (5) PH of unknown mechanisms or resulting from multiple factors, involving disorders that cannot be classified into the above four categories^[5-7]. Despite of the distinct etiological differences among these types, they collectively exhibit the pathological feature of pulmonary vascular remodeling, including intimal hyperplasia or fibrosis, medial smooth muscle thickening, and adventitial lesions. These changes further lead to plexiform vascular lesions and occlusion of small pulmonary arteries, significantly increasing pulmonary vascular resistance and ultimately causing right heart failure^[8].

The core mechanism of PH pathogenesis lies in the pathological remodeling of the pulmonary vascular system, particularly changes in small arteries^[9]. This process is not an independent behavior of a single cell type but involves complex dynamic interactions between pulmonary arterial endothelial cells (PAECs), pulmonary arterial smooth muscle cells (PASMCs), fibroblasts, immune cells, and extracellular matrix (ECM) components^[10]. It is mainly characterized by abnormal proliferation and apoptosis resistance of PASMCs, leading to medial hypertrophy; endothelial dysfunction-driven intimal hyperplasia and plexiform lesion formation; local coagulation imbalance causing in situ thrombosis; and accompanying perivascular inflammatory cell infiltration and interstitial fibrosis^[11-13].

Currently, PH treatment strategies mainly focus on improving the imbalance of soluble vasoactive mediators, such as excessive endothelin-1 (ET-1) production, inhibition of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathways, and decreased prostacyclin (PGI₂) synthesis^[1,13]. Although these treatments have shown some success in alleviating vasoconstriction, they are still inadequate to reverse structural vascular lesions, suggesting that modulating vascular tone alone is insufficient to effectively halt the progression of PH. In contrast, targeting integrins offers a novel approach that not only addresses vascular tone but also directly modulates the underlying vascular remodeling in PH. This innovative therapeutic strategy has the potential to reverse pathological ECM deposition and restore vascular homeostasis, representing a significant step beyond traditional vasodilator therapies.

Recent studies indicate that dynamic changes of the ECM and the mechanical signal perception system play crucial roles in driving persistent pulmonary vascular remodeling^[14,15]. Stimulated by factors such as chronic hypoxia, inflammation, abnormal shear stress, or genetic predisposition, the pulmonary vascular microenvironment undergoes significant changes, manifested as abnormal deposition of ECM components like fibronectin, collagen, and tenascin-C, increased matrix stiffness, and degradation imbalance^[16]. These physical and biochemical signals are sensed by cells via specific receptors, especially integrins, thereby activating downstream signaling networks^[14,17]

Integrins are key transmembrane receptors that connect cells to the ECM^[18,19]. Apart from mediating cell adhesion and anchorage, integrins also act as signaling hubs that regulate cell proliferation, migration, phenotype transformation, and survival^[20]. Under the pathological conditions of PH, specific integrin subtypes (e.g., α5β1, αvβ3, αvβ5) are upregulated in PASMCs and PAECs, activating downstream signaling pathways such as focal adhesion kinase (FAK), Src, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), and mitogen-activated protein kinase (MAPK), promoting abnormal cell proliferation and apoptosis resistance^[21-23]. Moreover, activation of certain integrins (e.g., αvβ6/αvβ8) may activate latent transforming growth factor-beta (TGF-β), thereby amplifying fibrosis and inflammation^[24-27]. Integrins also interact with other mechanosensitive pathways that influence pulmonary vascular remodeling—most notably the Hippo/YAP (Yes-associated protein) pathway. In PH, elevated ECM stiffness promotes integrin activation and downstream FAK signaling, which inhibits the Hippo pathway, leading to nuclear translocation of the transcriptional co-activators YAP/TAZ (transcriptional co-activator with PDZ-binding motif) to promote the transcription of genes related to cell proliferation, survival and fibrosis. Critically, YAP/TAZ also feedback to upregulate integrin and matrix components, increasing ECM stiffness and further amplifying integrin signaling. This bidirectional crosstalk establishes a self-sustaining vicious cycle that continuously aggravates pulmonary vascular remodeling in PH^[28-30]. Therefore, integrin-mediated “cell-ECM crosstalk" is not only an important regulatory factor in vascular YAP/TAZ structural remodeling but also provides a potential breakthrough for the development of novel therapeutic strategies targeting structural lesions.

This review comprehensively summarizes the latest research on integrin signaling in PH, discusses the dysregulation of specific integrin subtypes in pulmonary vasculature, introduces the main downstream signaling pathways, explores their interactions with growth factors and inflammatory mediators, and evaluates the therapeutic potential of targeting integrins and their effectors. Additionally, we highlight the challenges in translating these insights into clinical practice and future research directions.

Integrins are a group of widely expressed, heterodimeric transmembrane glycoprotein receptors on the cell surface, formed by non-covalent bonding between α and β subunits^[31]. Since their discovery in 1980s, research has shown that mammals express at least 18 α subunits and 8 β subunits, which combine to form 24 different integrin subtypes^[32,33]. Each integrin subunit typically consists of a large extracellular domain for ligand binding, a single transmembrane helix, and a short cytoplasmic tail that links to intracellular signaling and structural proteins^[34] [Table 1].

According to the different ligands identified, integrins are classified into four categories [Table 2]^[19,103,104]:

1. Arginine-glycine-aspartic acid (RGD)-binding integrins (the largest group), such as αvβ3, α5β1, and αIIbβ3, which recognize RGD motif in ECM components like fibronectin, fibrillin, and fibrinogen.

2. Leukocyte adhesion integrins, including β2 integrins (e.g., αLβ2, αMβ2) and members of the α4/α9/αE subfamily (e.g., α4β1, α4β7, α9β1, αEβ7), which mediate adhesion and migration of immune cells.

3. Collagen-binding integrins (e.g., α1β1, α2β1, α10β1, α11β1), which bind to collagen fibers through the GFOGER-like sequence and rely on the organizational structure of collagen fibers.

4. Laminin-binding integrins (e.g., α3β1, α6β1, α7β1, α6β4), which interact with laminin in the basement membrane.

Notably, some collagen-binding integrins (e.g., α1β1, α2β1, α10β1) also show affinity for laminin, suggesting potential functional overlap^[31]. Additionally, integrin expression is tightly regulated by tissue specificity and developmental stage. Apart from canonical ECM mediators, integrins also interact with non-ECM ligands, including pathogen-derived surface proteins, growth factors, hormones, and bioactive compounds^[105-107].

The function of integrins depends on maintaining a delicate balance between their active and inactive states through various mechanisms, including protein-protein interactions, conformational changes, and transport^[108,109]. In their initial state, integrins exist on the cell surface in an inactive, low-affinity conformation. Integrin activation is typically triggered by intracellular signals, a process known as "inside-out" signaling. During this process, proteins like talin and kindlin bind to the intracellular tail of the β-integrin subunit, disrupting the transmembrane structure and inducing a conformational change in the integrin to form a high-affinity, extended state. In this state, integrins bind specific ECM ligands like fibronectin, collagen, or laminin^[110-112].

After ligand binding, integrins aggregate and initiate “outside-in” signaling, a more complex and tightly regulated process. The intracellular domains of aggregated integrins serve as scaffolds for recruiting various adaptor proteins, including talin, vinculin, paxillin, and FAK^[113-115]. These proteins typically contain phosphotyrosine-binding domain or four-point-one, ezrin, radixin, moesin domain domains that recognize phosphorylation sites or structural changes at adhesion sites^[116-118]. The resulting large protein complexes, known as focal adhesion complexes (FACs), act as central hubs for signal transduction, activating downstream pathways such as FAK-Src, PI3K-Akt, and MAPK. These signaling pathways regulate diverse cellular functions such as adhesion, migration, proliferation, survival, and differentiation^[119-121].

Notably, integrin activation in PH is not solely regulated by biochemical cues but is strongly influenced by the mechanical stiffness of the ECM. Progressive ECM remodeling in PH, characterized by excessive collagen and fibronectin deposition, leads to increased matrix stiffness, which enhances mechanical force transmission across integrin-ECM bonds. This elevated mechanical tension stabilizes integrins in their active, extended conformation, promotes integrin clustering, and amplifies outside-in signaling even in the absence of strong inside-out activation. Consequently, mechanosensitive pathways such as FAK, YAP/TAZ, and TGF-β signaling are persistently activated, driving smooth muscle cell proliferation, endothelial dysfunction, and fibrosis. While these cellular responses further exacerbate ECM remodeling and stiffening, forming a vicious cycle that sustains pathological vascular remodeling in PH.

The complex signaling network formed by integrins and their associated proteins illustrates the multifunctionality of integrins in mediating dynamic interactions between cells and the ECM, and in responding to biochemical and mechanical signals within the microenvironment^[20]. Recent studies have further revealed that integrins not only play a key role in cell adhesion and migration, but also participate in many physiological and pathological processes by influencing cell morphology, metabolism, proliferation, apoptosis and other processes, especially playing an important role in the progression of diseases such as PH^[111] [Figure 1].

The unique heterodimeric structure and conformational plasticity of integrin lay the foundation for their dual role as adhesion receptors and mechanosensors. Importantly, these structural features are not merely static properties but are tightly linked to intracellular signaling events. Understanding how integrin conformational shifts are translated into biochemical signals is therefore essential for elucidating their role in pulmonary vascular remodeling. In this section, we outline the major integrin-mediated signaling pathways that have been implicated in the pathogenesis of PH.

In PH, pulmonary vascular lesions are closely associated with abnormal deposition of ECM components^[28]. Under stimuli such as hypoxia, inflammation, shear stress, and genetic predisposition, the pulmonary vascular microenvironment undergoes significant changes, manifesting as abnormal deposition of ECM components like fibronectin, collagen, and tenascin-C, leading to matrix stiffening and increased rigidity^[122-124]. This pathological ECM remodeling provides favorable conditions for the overexpression and sustained activation of integrins.

In PH, pulmonary vascular lesions are closely associated with abnormal deposition of ECM components^[28]. Under stimuli such as hypoxia, inflammation, shear stress, and genetic predisposition, the pulmonary vascular microenvironment undergoes significant changes, manifesting as abnormal deposition of ECM components like fibronectin, collagen, and tenascin-C, leading to matrix stiffening and increased rigidity^[122-124]. This pathological ECM remodeling provides favorable conditions for the overexpression and sustained activation of integrins.

Studies have shown that in patients with PH and animal models, abnormally upregulated integrin subtypes such as α5β1, αvβ3, and αvβ5 are closely related to pulmonary vascular remodeling^[22,125]. However, the expression and dysregulation of these integrins may vary across different PH subtypes. For example, in PAH, characterized by endothelial dysfunction and excessive smooth muscle cell proliferation, αvβ3 and α5β1 are particularly prominent, promoting cell proliferation and resistance to apoptosis^[126]. In contrast, in CTEPH, where fibrotic occlusion of large pulmonary arteries predominates, integrin β2 (ITGB2) is increasingly implicated. Recent reports have found that ITGB2 is upregulated in platelets/immune cells in patients with CTEPH, which is related to the formation of neutrophil extracellular trap (NET) and the maintenance of inflammation, which may indirectly promote thrombus solidification and the progression of the disease course^[127]. In addition, hypoxia—a key environmental driver of PH—further modulates integrin expression across subtypes via the HIF-1α signaling pathway^[128], thereby directly linking external stress to integrin-mediated vascular remodeling. These subtype-specific patterns underscore the need for precision therapeutic strategies that target the most relevant integrin pathways according to the underlying etiology of PH.

Upon activation, integrin not only mediates the physical anchorage of cells to the ECM but more importantly, through the assembly of FACs, initiates a series of complex intracellular signaling cascades^[31]. These signaling pathways play a crucial role in the pathological processes of PH, promoting abnormal proliferation, apoptosis resistance, migration, phenotype transformation, and inflammatory responses of PASMCs and ECs, ultimately leading to pulmonary vascular remodeling [Figure 2].

With the deepening of research into the pathogenesis of PH, the role of the ECM and mechanotransduction systems in pulmonary vascular remodeling has received increasing attention^[15]. As a key molecule linking cells to the ECM, integrins play an important role in the pathology of PH^[22]. Although integrin signaling has been shown to play a crucial role in PH pathogenesis, the current challenge lies in how to translate these findings into effective clinical treatments.

There are many members of the integrin family, and their functions and expression differ significantly across different tissues^[31]. Therefore, accurately identifying specific integrin subtypes associated with PH and developing highly selective inhibitors is critical for avoiding off-target effects and reducing side effects. Additionally, it is necessary to gain a deeper understanding of the specific roles of each subtype in different types of PH to achieve precision therapy.

While several integrin inhibitors have made progress in oncology and fibrotic diseases, clinical validation in PH is still in the early stages^[177,178]. One major barrier to clinical translation in PH is efficacy concerns, as integrin inhibitors have shown limited success in targeting vascular remodeling in PH. Furthermore, biomarker limitations in PH complicate patient stratification, making it difficult to identify those most likely to benefit from integrin-targeted therapies. Off-target effects, particularly in the cardiovascular system, may also contribute to safety concerns. These challenges highlight the need for further research into integrin inhibitor efficacy in PH and the development of reliable biomarkers to guide patient selection for future trials.

Importantly, the limited success of certain integrin inhibitors in oncology trials offers valuable insights for their potential application in PH. For instance, Cilengitide—a cyclic RGD peptide targeting αvβ3 and αvβ5—exhibited promising anti-angiogenic activity in preclinical tumor models yet failed to deliver significant survival benefits in Phase III clinical trials for glioblastoma. Several key factors have been implicated in this outcome, including inadequate biomarker-guided patient stratification, functional redundancy among integrin subtypes, and paradoxical pro-angiogenic effects at suboptimal dosing concentrations^[179]. These clinical experiences hold profound relevance for PH translational research. In contrast to oncology, PH is a chronic progressive disorder requiring long-term therapeutic intervention, where safety profiles, rational dosing strategies, and sustained target engagement are of particular importance. Furthermore, the inherent heterogeneity of PH suggests that only distinct patient subgroups—such as those with marked integrin overexpression or ECM-driven vascular remodeling—are likely to derive clinical benefit from integrin-targeted therapies^[180]. Therefore, successful translation of such agents in PH will likely hinge on improved biomarker-based patient selection, disease-stage-specific therapeutic intervention, and meticulous optimization of dosing regimens to mitigate off-target effects or compensatory signaling pathways.

Systemic administration of integrin inhibitors may lead to severe side effects, particularly in the cardiovascular system^[181]. Therefore, improving the delivery efficiency of drugs to the lungs and reducing systemic side effects is key to achieving clinical translation. Nanotechnology, liposomes, and other targeted delivery systems provide new approaches to solving this problem. For example, nanoparticles surface-modified with RGD peptides or anti-PECAM antibodies actively targets activated endothelial cells, enabling localized drug accumulation^[182,183]. Moreover, inhaled formulations (such as nebulized inhalers) also represent a potential delivery method, directly acting on the pulmonary lesions and reducing systemic exposure^[173].

Biomarkers and treatment responses in different types of PH patients show significant differences. For instance, some patients may exhibit overexpression of specific integrin subtypes, while others may rely on different signaling pathways (e.g., PDGF, VEGF)^[23,126]. Developing individualized treatment plans based on molecular characteristics remains an urgent challenge.

Looking ahead, the development of imaging-based and circulating biomarkers reflecting integrin expression or activation status may provide powerful tools for patient stratification in PH. While direct clinical evidence supporting circulating soluble integrin ectodomains as validated biomarkers remains limited, increasing attention has focused on ECM-derived peptides—such as collagen degradation neo-epitopes and matrikines—which reflect pathological matrix turnover and vascular fibrosis. Several studies in PH and related fibrotic diseases have demonstrated that these ECM fragments correlate with disease severity and hemodynamic impairment^[184-186]. In parallel, integrin-targeted molecular imaging approaches, including αvβ3-directed PET tracers, are being explored to enable non-invasive assessment of regional vascular remodeling and integrin activation in vivo, highlighting an emerging translational framework for biomarker-guided precision therapy.

Despite the multiple challenges currently faced in the study of integrins in PH, their emerging role as a therapeutic target offers unprecedented treatment potential. Through further basic research and clinical trials, we expect to see integrin-targeted therapies become a new option for PH treatment. By combining modern molecular biology techniques and drug delivery systems, integrin-targeted therapies not only have the potential to slow vascular remodeling but also reverse the structural damage caused by PH, offering patients better prognosis.

Integrin signaling pathways play a central role in the pathogenesis of PH, driving vascular remodeling through their impact on cell proliferation, survival, inflammation, and ECM dynamics. Dysregulation of integrin expression and abnormal activation of downstream signaling pathways (such as FAK, PI3K/Akt, and MAPK) create a favorable environment for disease progression. While current treatments mainly target vasoconstriction, integrin-targeted therapies offer a strategy to address the structural basis of PH. Integrin-targeted strategies not only alleviate vasoconstriction but may also reverse structural remodeling, representing a paradigm shift in PH therapeutics. Although clinical translation faces obstacles, advances in selective inhibitors and delivery systems hold promising potential. A deeper understanding of integrin biology in PH is essential for developing effective disease-modifying therapies.