Vascular cells are continuously exposed to mechanical forces, including matrix stiffness, shear stress from blood flow, and cyclic stretch from pulsatile pressure during the cardiac cycle^[21-24]. YAP/TAZ integrate these diverse mechanical cues to coordinate vascular homeostasis and remodeling. For example, cyclic stretch induces YAP nuclear translocation via the Thbs1/integrin αvβ1-Rap2-Hippo pathway in vascular smooth muscle cells (VSMCs), and YAP/TAZ are required for stretch-induced proliferative and pro-inflammatory responses^[21,22,24].

Vessels play vital roles in supplying oxygen and nutrients to tissues throughout the body, making vascular cells sensitive sentinels of metabolic stress. Their metabolic state reflects local nutrient and oxygen availability and can signal tissue hypoxia. YAP/TAZ have emerged as important integrators that couple these metabolic cues to vascular adaptation: they are regulated by nutrients (glucose, fatty acids, insulin) and, in turn, regulate key metabolic pathways including glycolysis, lipogenesis, and glutaminolysis. Through this bidirectional circuit, YAP/TAZ align metabolic activity with vascular homeostasis and tissue repair^[11].

Classical cardiovascular risk factors - including hypertension, diabetes mellitus, dyslipidemia, and obesity - intersect with YAP/TAZ signaling through cell-type-specific mechanisms. In hypertension, YAP/TAZ are essential for maintaining vascular tone, and their dysregulation promotes hypertensive vascular remodeling via Foxm1 upregulation^[50]. In diabetes, hyperglycemia activates YAP/TAZ signaling, promoting endothelial inflammation and monocyte-EC attachment^[51]. The mevalonate pathway activates YAP/TAZ through geranylgeranylation-dependent Rho GTPase signaling^[46,47]. Separately, macrophage YAP/TAZ-BRD4 signaling promotes inflammatory activation and oxidized Low-density Lipoprotein (oxLDL) uptake/lipid accumulation, contributing to atherogenesis^[52]. In obesity, a high-fat, high-sucrose diet sustains YAP-mediated TGF-β signaling, exacerbating arterial stiffness^[42]. Notably, despite their well-established roles as cardiovascular risk factors, direct mechanistic evidence linking lipoprotein(a) or homocysteine to YAP/TAZ signaling remains limited and warrants direct investigation. These associations are summarized in Table 1.

Regulation of proliferation and migration. Beyond pathological angiogenesis, YAP/TAZ play essential roles in physiological vascular development. Endothelium-specific YAP/TAZ knockout models show that YAP/TAZ activity is required for developmental sprouting angiogenesis^[53,54]. Mechanistically, YAP/TAZ support stretch-induced endothelial proliferation and rearrangement, preserve developing vessels, and are required for tip cell migration and stalk cell proliferation during sprouting angiogenesis^[53,54]. The focal adhesion protein DLC1, a YAP-induced RhoGAP, suppresses Rho-mediated cytoskeletal tension, establishing a mechanosensitive feedback loop that limits YAP nuclear localization and fine-tunes angiogenic sprouting^[55]. In brain arteriovenous malformations, YAP expression decreases but rises following embolization, indicating reactivation of Hippo-YAP signaling during vascular repair^[56]. Recent work has also identified the tight junction-associated protein Pals1-associated Tight Junction Protein (PATJ) as a novel regulator of YAP1 in endothelial stress responses. PATJ is upregulated in endothelial cells after ischemic stroke, and its deletion alters YAP1 nuclear translocation and dysregulates genes involved in vascular development, including RUNX1 (Runt-related transcription factor 1) and HEY1 (Hairy/enhancer-of-split related with YRPW motif 1), as well as stress response genes such as NUPR1 (nuclear protein 1)^[57]. Beyond mechanical cues, YAP also intersects with TGF-β signaling to regulate endothelial-mesenchymal transition (EndMT). By stabilizing SMAD family member 3 (SMAD3) against glycogen synthase kinase 3 beta (GSK3β)-dependent degradation, YAP forms a transcriptional complex with SMAD3 that directly activates EndMT target genes, thereby promoting pathological vascular remodeling^[58].

Inflammatory activation and barrier function. YAP drives endothelial inflammation through multiple mechanisms. Upon oscillatory shear stress or tumor necrosis factor-alpha (TNF-α) stimulation, YAP forms a complex with BTB and CNC homology 1 (BACH1), which is required for the induction of adhesion molecules and endothelial inflammation^[59]. In diabetes-accelerated atherosclerosis, high glucose and oxLDL promote G protein subunit alpha i2 (GNAI2) S-nitrosylation, enhancing C-X-C chemokine receptor type 5 (CXCR5) coupling to reduce cyclic adenosine monophosphate (cAMP), thereby inactivating the LATS1-YAP axis and driving pro-inflammatory transcription^[60]. Pharmacological evidence supports the functional relevance of this pathway. Verteporfin-mediated YAP/TAZ inhibition in a progeria model significantly reduced vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and P-selectin expression, decreasing leukocyte adhesion^[61]. These endothelial changes can alter monocyte recruitment and thereby influence inflammation, angiogenesis, and tissue remodeling^[62].

Substrate stiffening, a hallmark of vascular disease, reduces tuberous sclerosis complex 2 (TSC2) abundance in pulmonary arterial smooth muscle cells, allowing YAP/TAZ accumulation and mechanistic target of rapamycin (mTOR) activation to drive proliferation. The remodeled ECM amplifies this signal in neighboring cells via α5β1-integrin^[63]. In a related endothelial model using engineered hydrogels, stress-relaxation and gelatin mechanics activate a YAP-dependent transcriptional program that promotes endothelial remodeling. In this context, αvβ3 integrin and matrix metalloproteinase 2 (MMP2) coordinate matrix degradation and reorganization to enable vasculogenesis both in vitro and in vivo^[64].

Vascular smooth muscle cells maintain vessel tone and adapt to hemodynamic changes through phenotypic plasticity. YAP and TAZ regulate genes involved in smooth muscle differentiation and contraction, with smooth muscle-specific deletion or genetic ablation of YAP/TAZ leading to reduced contractility, impaired myogenic response, increased vascular compliance, and downregulation of differentiation markers such as Acta2, Tagln, and Myh11 in the arterial media^[21,65]. These contractile functions contribute directly to blood-pressure regulation. Inducible deletion of YAP/TAZ in adult smooth muscle cells results in impaired agonist-stimulated contractility and hypotension^[21,66]. The importance of YAP/TAZ in VSMCs is supported by in vivo genetic models, as summarized in Table 2.

Dysregulation of YAP/TAZ in VSMCs has been directly linked to clinically significant vascular wall pathologies. For instance, vascular smooth muscle-specific YAP/TAZ deletion triggers spontaneous development of abdominal aortic aneurysms, accompanied by pronounced VSMC apoptosis and matrix degradation, providing genetic evidence that YAP/TAZ are essential for maintaining aortic structural integrity^[67]. Similarly, inducible deletion of YAP/TAZ in smooth muscle cells predisposes mice to aortic dissection and rupture under hemodynamic stress^[68]. Together, these findings connect YAP/TAZ dysfunction to life-threatening large-vessel disease and link vascular mechanobiology to clinically relevant pathology.

Upon vascular injury or hemodynamic stress, YAP expression increases, promoting VSMC dedifferentiation and intimal hyperplasia^[69]. In saphenous vein grafts, mechanical forces synergize with TGF-β/thrombospondin-1 (TSP-1) signaling to activate YAP, which drives a fibrotic response in resident progenitor cells and contributes to graft failure^[70]. Disturbed flow activates VSMCs through Piezo1, which converts flow into Ca²⁺ signals that activate Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) and calcineurin, promoting YAP/TAZ-dependent proliferation and migration^[71]. In contrast, G protein-coupled receptor 153 (GPR153) deficiency elevates cAMP and activates LATS1/2-mediated phosphorylation of YAP/TAZ, leading to their degradation and impaired VSMC dedifferentiation^[72].

YAP/TAZ contribute to diverse VSMC-related pathologies through context-dependent mechanisms. In vascular calcification, YAP/TAZ have apparently opposing effects. Basal YAP/TAZ activity restrains osteogenic transdifferentiation, because their deletion activates a DVL3-dependent Wnt cascade that induces ectopic calcification^[65]. By contrast, in the OTU deubiquitinase 2 (OTUB2) pathway, stabilized YAP promotes VSMC osteogenic differentiation by forming a transcriptional complex with TEAD1 that directly binds to the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) promoter and enhances its expression, thereby promoting vascular calcification^[73]. YAP also drives pathological remodeling in pulmonary arterial hypertension, where LATS1 inactivation establishes a self-sustaining YAP/fibronectin/integrin-linked kinase 1 (ILK1) loop that activates mTOR-Protein Kinase B (Akt), suppresses apoptosis, and sustains VSMC proliferation^[74]. In neointimal hyperplasia following arterial interventions, YAP activity is negatively regulated by Tax1-binding protein 3 (TAX1BP3), which competes for TEAD binding; therapeutic delivery of TAX1BP3 via adeno-associated virus (AAV) or nanoparticles effectively reduces vascular remodeling^[75]. In the context of physiological vascular homeostasis, YAP/TAZ mechanosensing is paramount for maintaining vascular integrity throughout life. Notably, YAP/TAZ activity decreases with age in mice, which results in cGAS (cyclic GMP-AMP synthase) - STING (stimulator of interferon genes)-induced vascular inflammation and may provide a mechanistic link between aging and vascular dysfunction^[68,76,77]. These findings indicate that the effect of YAP/TAZ on VSMC fate depends on baseline activity, upstream regulation, and disease context.

Beyond endothelial and smooth muscle cells, YAP/TAZ orchestrate the behavior of perivascular and immune cells that collectively shape the vascular microenvironment. In the vascular adventitia, where fibroblasts are the predominant cell type^[78], YAP1 activation drives their transition into migratory myofibroblasts and enhances collagen deposition, thereby promoting abdominal aortic aneurysm (AAA) formation^[79]. Within perivascular adipose tissue (PVAT), dysregulation of the PGC1α-YAP axis disrupts smooth muscle protein 22-alpha (SM22α)-lineage stromal cell differentiation, leading to aberrant PVAT remodeling and AAA development^[80]. In TSC, loss of TSC1/TSC2 causes mTOR hyperactivation and impaired autophagic degradation, resulting in YAP accumulation that drives proliferation of perivascular epithelioid cell tumors (PEComas)^[81]. In developmental bone formation, YAP/TAZ direct the coordinated mobilization of osteoblast precursors and blood vessels via CXCL12 signaling, facilitating essential processes including hypertrophic cartilage degradation and load-induced ossification^[82].

YAP also contributes to bidirectional communication between vascular and immune cells. In antiphospholipid syndrome, patient-derived IgG activates Toll-like receptor 4 (TLR4)-YAP1 signaling in ECs, inducing CCN2 expression that subsequently drives VSMC proliferation and neointima formation via epidermal growth factor receptor (EGFR)^[83].

Within the immune compartment, YAP/TAZ shape macrophage phenotype and function. Stanniocalcin-1 activates YAP through competitive p21-activated protein kinase exchange factor beta (βPIX) binding, establishing a CCL2-mediated feedback loop that promotes M2 polarization, angiogenesis, and programmed death ligand 1 (PD-L1)-dependent immune evasion in melanoma^[84]. Mechanical cues further modulate macrophage YAP activity: moderate mechanical strain (~15%) optimally activates YAP/TAZ, driving M2 polarization and enhancing wound healing through paracrine-mediated angiogenesis^[85]. In pulmonary fibrosis, macrophage YAP/TAZ promote disease progression through two mechanisms: CCL2-mediated recruitment of monocyte-derived alveolar macrophages and MBD2-TGF-β1-pSMAD2-dependent signaling that induces fibroblast-to-myofibroblast transition^[86]. Conversely, intracellular lipopolysaccharide (LPS) induces gasdermin D (GSDMD)-mediated mitochondrial damage and mtDNA release, which activate the cGAS-STING pathway to inhibit YAP dephosphorylation and nuclear translocation, ultimately suppressing cyclin D expression and endothelial proliferation^[87].

YAP/TAZ regulate macrophage polarization within the vascular microenvironment. Expression of YAP and TAZ is increased in macrophages undergoing both M1 and M2 polarization^[88]. Mechanistically, YAP/TAZ promote M1 (pro-inflammatory) polarization by increasing IL6 expression, while impeding M2 (anti-inflammatory) polarization by decreasing Arg1 expression through interaction with the histone deacetylase 3 (HDAC3)-nuclear receptor corepressor 1 (NCoR1) repressor complex^[88]. Genetic deletion of YAP/TAZ leads to impaired M1 polarization and enhanced M2 polarization, resulting in reduced inflammation^[88]. In the context of atherosclerosis, YAP/TAZ activation in macrophages promotes pro-inflammatory cytokine production and plaque progression. Conversely, inhibition of YAP/TAZ suppresses inflammatory gene expression and macrophage infiltration^[52,89]. Mechanical cues, including matrix stiffness and cyclic stretch, further modulate macrophage polarization through YAP/TAZ-dependent pathways^[90]. Together, these findings link YAP/TAZ-dependent macrophage plasticity to mechanical signals and vascular inflammation. The divergent M1- and M2-associated effects reported across models likely reflect differences in tissue context, stimulus type, magnitude, and duration.

Collectively, these findings illustrate that YAP/TAZ not only orchestrate cell-autonomous functions but also coordinate intercellular crosstalk among endothelial cells, smooth muscle cells, fibroblasts, and macrophages. This YAP/TAZ-mediated communication network integrates mechanical, metabolic, and inflammatory signals across the vascular wall, ensuring coordinated responses to physiological demands and pathological insults.

Several approved lipid-lowering agents suppress YAP/TAZ transcriptional activity in experimental models. Inflammatory signaling also intersects bidirectionally with YAP/TAZ in the vasculature. Pro-inflammatory cytokines such as interleukin-6 (IL-6) and TNF-α can activate YAP/TAZ through noncanonical pathways^[91,92], while YAP/TAZ in turn regulate pro-inflammatory gene programs in endothelial cells^[93] and VSMCs^[67,68]. Among anti-inflammatory drugs with cardiovascular benefits, colchicine has been shown to activate Hippo signaling and promote YAP phosphorylation in cardiomyocytes, and its microtubule-depolymerizing activity is known to regulate YAP/TAZ nuclear-cytoplasmic shuttling^[94]; however, direct evidence for colchicine-YAP/TAZ modulation in vascular cells remains lacking. Similarly, no direct studies are available for canakinumab or tocilizumab regarding YAP/TAZ, although fundamental evidence suggests that IL-6 can activate YAP^[95], supporting a testable hypothesis rather than a therapeutic conclusion^[96,97]. A high-throughput screen of 640 U.S. Food and Drug Administration (FDA)-approved compounds identified statins as inhibitors of YAP/TAZ signaling^[46]. Mechanistically, YAP/TAZ activity depends on the sterol regulatory element-binding protein (SREBP)-mevalonate pathway: statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, reducing geranylgeranyl pyrophosphate synthesis and preventing RhoA activation, thereby blocking YAP/TAZ nuclear localization^[46]. Lipophilic statins further promote cytoplasmic sequestration of YAP through Rho GTPase-dependent cytoskeletal remodeling, independent of their lipid-lowering effects^[97]. Consistently, simvastatin inhibits geranylgeranyl transferase I (GGTase I), blocking RhoA-driven YAP nuclear import, suppressing SRY-box transcription factor 9 (SOX9)-mediated EndMT, and preserving vascular function independent of cholesterol lowering^[98]. Notably, simvastatin failed to suppress pro-inflammatory gene expression induced by constitutively active YAP/TAZ in endothelial cells, indicating that inhibition of endogenous YAP/TAZ may underlie the anti-inflammatory benefits of statins^[99]. The approved photosensitizer verteporfin also inhibits YAP by increasing cytosolic 14-3-3σ and trapping YAP in the cytosol^[100]. When encapsulated in biomimetic nanoparticles, verteporfin achieves lesion-specific YAP/TAZ inhibition, attenuating atherosclerosis while avoiding off-target effects associated with systemic YAP/TAZ modulation^[89].

Beyond drug repurposing, recent efforts have focused on developing novel small molecules that target YAP/TAZ signaling through distinct mechanisms. One approach targets the mevalonate pathway upstream of YAP: the GGTase-I inhibitor BAY-593, identified via high-throughput screen of 3.8 million compounds, blocks Rho GTPase activation and potently inhibits YAP/TAZ signaling in vivo, providing an additional upstream strategy^[101]. Another strategy directly disrupts the YAP/TAZ-TEAD transcriptional complex. The small-molecule inhibitor GNE-7883 allosterically binds the TEAD lipid pocket, disrupting YAP/TAZ-TEAD interactions and suppressing chromatin accessibility at TEAD motifs^[102]. Early clinical data with the TEAD palmitoylation inhibitor VT3989 provide proof of concept for direct YAP-TEAD pathway inhibition in oncology^[103]. More recently, a protein degradation approach has been developed using a YAP-targeting bioPROTAC that fuses a camelid nanobody with the ring finger protein 4 (RNF4) RING domain to degrade endogenous YAP via the ubiquitin-proteasome system^[104]. Multiple Hippo pathway-targeted therapies are in development, with several already undergoing clinical trials^[105].

Most YAP/TAZ-targeted agents remain in oncology development, with VT3989^[103] (NCT04665206), IAG933 (NCT04857372), and verteporfin^[106] (NCT06381154) showing early promise in solid tumor trials. Cardiovascular translation is nascent: the phase 1 SALVADOR-HF trial (NCT06831825) is evaluating YAP101, an AAV-based gene therapy for ischemic heart failure. However, direct evidence for small-molecule YAP/TAZ modulators in cardiovascular disease remains lacking, and future work should prioritize vascular-targeted delivery to achieve lesion-specific modulation.

Despite these promising advances, translating YAP/TAZ-targeting strategies into vascular therapies faces several interrelated challenges that require careful consideration. First, YAP/TAZ can be protective or pathogenic depending on cell type, vascular bed, and disease stage. Systemic inhibition could therefore impair tissue homeostasis or regeneration while suppressing a lesion-specific pathway. Second, current agents generally lack the spatial and cellular selectivity required to modulate endothelial, smooth muscle, stromal, and immune compartments differently. Third, clinical validation is limited. YAP/TAZ activity has not been robustly linked to imaging-defined atherosclerotic burden or cardiovascular outcomes, partly because nuclear localization and phosphorylation are difficult to measure in routine specimens and no validated circulating surrogate is available. Progress will require vascular-targeted delivery, context-selective interaction partners, and pharmacodynamic biomarkers. Molecular imaging, prospective analysis of human vascular specimens, and single-cell or spatial profiling could map pathway activity across cell types and lesion stages. These approaches should be paired with outcome studies and explicit safety assessment.