Vascular remodeling within the developing fetus and placenta is essential for supporting the growth and function of emerging tissues and organs. Pericytes (PCs) play a central role in stabilizing and maturing microvascular networks by extending along endothelial cells (ECs) and reinforcing vessel integrity. In the placenta, as in other organs, PC–EC communication is mediated in part by platelet-derived growth factor-BB (PDGF‑BB) signaling, which governs PC differentiation, proliferation, migration, and survival, ultimately enabling their recruitment and retention along capillaries. In this study, we identified progressive PC investment along feto‑placental capillaries in both murine and human tissues across gestation, supported by morphological and molecular evidence. Placental PCs displayed phenotypic heterogeneity comparable to that observed in the brain and heart, suggesting conserved diversity across organ systems. In addition to characterizing PC dynamics, we examined the expression of recently identified soluble PDGF Receptor-β (sPDGFRβ) isoforms. These variants were detected at the protein and transcript levels in mouse and human placentas, as well as in a murine trophoblast‑embryonic stem cell (TESC) differentiation model that recapitulates aspects of early placental vascular development. Within this model, sPDGFRβ expression was independent of ADAM10 activity and exogenous growth factors during early vessel formation but was markedly upregulated during hypoxia. To assess how elevated sPDGFRβ might influence PDGF‑BB signaling, we exposed TESC‑derived vascular networks to excess PDGF‑BB with or without a sPDGFRβ mimetic. PDGF‑BB alone reduced full‑length PDGFRβ levels while increasing receptor phosphorylation, consistent with known ligand‑induced regulatory mechanisms. Inclusion of the sPDGFRβ mimetic shifted these responses toward baseline, suggesting a potential modulatory or feedback role for soluble receptor variants. Together, these findings demonstrate that PCs are progressively recruited to placental capillaries and exhibit diverse phenotypes during development, and that soluble PDGFRβ isoforms may modulate PDGF‑BB signaling in a manner sensitive to oxygen tension. Understanding these mechanisms provides insight into the regulation of placental vascular maturation and may inform strategies to improve human health by targeting disorders rooted in impaired placental development.
Total paucity exists on how large human blood vessels respond to ischemia. We explored the human vascular response to trauma-induced ischemia, with a particular focus on vascular wall remodelling. Arterial and venous wall samples were analysed from 40 patients undergoing soft tissue free flap reconstruction following lower extremity trauma. Patients were stratified into an early reconstruction group (median 6 days post-injury (IQR 4–8); n = 26) after high-energy lower extremity open fracture, and a late reconstruction group (median 54 days post-injury (IQR 31–155); n = 14) operated due to fracture non-union or fracture related infection. Injury-site arterial and venous biopsy samples were collected at the anastomosis site during reconstruction, while control samples were obtained from intact blood vessels at free flap donor sites. Quantitative histological and immunohistochemical analyses were performed using QuPath software. The cohort consisted predominantly of working-age males (median age: early group 44 years, late 50 years; p = 0.72). Arterial intimal hyperplasia was significantly greater at injury sites than in the control arteries in both groups. Venous intimal thickening exceeded control levels by more than threefold. Adventitial angiogenesis was primarily observed in veins in the early reconstruction group, and it was more pronounced in both arteries and veins of the late group compared to the early group. Our findings demonstrate that major lower extremity trauma and trauma-induced ischemia trigger active remodelling across all layers of the vascular wall. The most prominent structural changes are linked to rapid onset of intimal hyperplasia and adventitial angiogenesis originating from the venous system.
Retinal diseases driven by pathological angiogenesis and vascular leakage, including neovascular age-related macular degeneration and diabetic retinopathy, impose substantial visual and treatment burdens because current anti-vascular endothelial growth factor (anti-VEGF) therapy requires repeated intravitreal administration. Ocular gene therapy can provide durable intraocular expression of therapeutic proteins and sustained pathway-level disease control. This systematic review and meta-analysis was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. PubMed, Scopus, Web of Science, ScienceDirect, and the Cochrane Library were searched from inception to April 21, 2026. Eligible studies included preclinical, in vitro, and clinical investigations of gene-based interventions targeting retinal angiogenesis, vascular permeability, or related anatomical and treatment-burden outcomes. Random-effects meta-analyses were performed using standardized mean differences (SMDs), mean differences (MDs), and logit event rates. Twenty-five studies were included. Preclinical gene therapy significantly reduced pathological neovascularization, with a pooled standardized mean difference (SMD) of −1.16 (95
Ischemic stroke is a global health crisis necessitating targeted therapeutic strategies. Central to post-stroke pathology and repair is the CXCL12 signaling axis. In this review, we discuss the context-dependent roles of CXCL12 and its canonical receptor, CXCR4, within the post-ischemic microenvironment. The CXCL12/CXCR4 axis exhibits a temporal duality across the evolution of the neurovascular lesion; however, current evidence necessitates moving beyond a strictly binary framework. While the acute phase involves pathological cascades, such as blood-brain barrier disruption and leukocyte infiltration, the axis is simultaneously essential for recruiting protective innate immune subsets. During subsequent subacute and chronic phases, it governs essential restorative processes, including neurogenesis, angiogenesis, and remyelination. This complex temporal shift is mediated by the interplay between distinct CXCL12 isoforms and the regulatory influence of the atypical receptor ACKR3/CXCR7. Furthermore, these endogenous repair mechanisms exhibit synergies with non-pharmacological interventions, notably environmental enrichment and remote ischemic postconditioning. Our multidimensional model suggests that the functional outcome of CXCL12/CXCR4 signaling is determined by the intersection of timing, cell type, receptor availability, and adaptive responses to physiological stimuli. We synthesize fundamental mechanistic data with translational insights to evaluate the therapeutic potential of this axis and the pharmacological barriers to future regenerative strategies.
mRNA localisation is a critical posttranscriptional mechanism that confers a spatiotemporal dimension to the control of gene expression. Among diverse outcomes, this process can result in compartmentalised protein synthesis and consequently, elicit localised cellular responses. Targeting mRNAs to their destination is often determined by localisation elements (LEs) contained in untranslated regions within targeted transcripts. Although mRNA localisation has been widely explored in the context of subcellular biology, its roles in tissue function are only just beginning to emerge. A defined set of transcripts accumulate at the leading edge of endothelial tip cells that guide emerging vessels during sprouting angiogenesis. This includes RAB13 and NET1 mRNAs, which encode proteins implicated in cytoskeletal remodelling processes underpinning cell motility. In this study, we tested the anti-angiogenic potential of antisense oligonucleotide (ASO)-based strategies designed to perturb RAB13 and NET1 localisation. Upon confirming that ASOs targeting LEs mislocalise these mRNAs without altering steady-state levels of the encoded proteins, we applied them to a series of in vitro, ex vivo and in vivo angiogenesis assays. Remarkably, the mislocalisation of RAB13 and NET1 inhibits chemotaxis and vessel sprouting in response to pro-angiogenic stimuli. Furthermore, vessel sprouting from mouse choroidal explants and retinal angiogenesis are also hindered by mRNA mislocalisation. Altogether, our strategy for disrupting spatial control of gene expression in endothelial cells opens new mechanistic avenues for the manipulation of vessel formation.
Venous malformation (VM) is the most common subtype of vascular malformation. Due to the chronic nature of this disorder, VM patients face significant morbidity and complications throughout their lives. Current therapeutic options can be limited, but recent advances in understanding the cellular and molecular mechanisms that underly VM pathogenesis provide hope for the discovery of more effective targeted therapies. These advances arise from a greater understanding of the cellular effects of VM-causative mutations, which has been aided by the development of more advanced and physiologically relevant model systems. In this review, we begin by providing a brief overview of the clinical characteristics and genetic driver mutations of the most common subtypes of all vascular anomalies (including vascular tumors and vascular malformations), providing context for our more detailed discussion of these aspects of VM. We further summarize the current treatment options available for VM patients and the advancements that have been made in the use of targeted therapies for these patients. We further discuss recent advances in the development of model systems that can be used to study VM pathogenesis. Finally, we focus this review on the mechanisms that are downstream of mutant TIE2, discussing structural features of the receptor, TIE2 signaling pathways, and its roles in vascular physiology and VM pathology.
Tumor progression depends on an adequate blood supply to sustain oxygen and nutrients delivery. While tumor angiogenesis involves the formation of new blood vessels from pre-existing ones, vessel co-option represents a non-angiogenic vascularization strategy whereby tumor cells utilize pre-existing host vessels. Co-opted vessels have been considered refractory to anti-angiogenic therapies, and pharmacological modulation of co-opted vessels remains limited. In this study, we investigate the effects of low-dose cilengitide on tumor vascular remodeling in vessel co-option and angiogenic metastatic models. Our results reveal that cilengitide exerts distinct vascular effects depending on the mode of tumor vascularization. In vessel co-option-driven tumors, cilengitide treatment is associated with the remodeling of the co-opted vasculature into a more organized normalized vascular network, characterized by an increased number of functional blood vessels and enhanced vascular barrier integrity. In contrast, in angiogenic-driven tumors, cilengitide treatment promotes an expansion of the vascular network consistent with augmented, but structurally immature angiogenesis. Importantly, vascular remodeling in vessel co-option metastases is accompanied by enhanced blood vessel perfusion and reduced hypoxia, which correlates with enhanced responsiveness to chemotherapy. Conversely, in angiogenic metastases, the vascular network induced by low-dose cilengitide fails to support immunocompetent microenvironmental features and is associated with increased chemotherapy resistance. This study provides the first evidence that co-opted vasculature can be therapeutically targeted via integrin inhibition, suggesting vascular normalization remodeling as a potential strategy to overcome resistance in tumors undergoing vessel co-option.
TIE2 is an endothelial receptor tyrosine kinase (RTK) essential for vascular integrity, and constitutively active TIE2 mutants are involved in venous malformations (VMs). VMs are currently treated by surgery or sclerotherapy, but effective pharmacologic options remain limited, especially for surgically challenging Blue Rubber Bleb Nevus Syndrome (BRBNS). TIE2 activation has typically been assessed by immunoblotting of phosphoproteins, yet scalable assays applicable to pharmacological evaluation are still lacking. Here, we present a bioluminescence resonance energy transfer (BRET) biosensor that quantifies receptor-proximal TIE2 activation by monitoring recruitment of GRB2, a major adaptor in RTK signaling. This BRET sensor detects angiopoietin-1 (ANG-1) at physiological plasma concentrations and is compatible with a high-throughput format. Furthermore, it captures constitutive activity of TIE2 mutants associated with VMs and enables pharmacological evaluation of TIE2 variants. Notably, the T1105N–T1106P variant, frequently observed in BRBNS, exhibited relatively higher sensitivity to the clinical oncology drugs regorafenib and lenvatinib. To validate selected BRET-defined pharmacological profiles in an endothelial context, we used HUVEC-derived HUEhT-2 cells and established endothelial TIE2–GRB2 BRET measurements, followed by downstream AKT/ERK signaling analysis and tube formation assays. These endothelial assays largely supported the selected HEK293T BRET findings, particularly the pharmacological profile of T1105N–T1106P mutant, at receptor-proximal, downstream signaling, and functional levels. Together, this BRET-based biosensor establishes a two-step framework: HEK293T BRET enables efficient primary profiling, whereas endothelial assays provide orthogonal validation to support biological interpretation. This framework offers a practical strategy for prioritizing pharmacological candidates for further endothelial and in vivo validation toward therapeutic development.
Thoracic aortic dissection (TAD) associates with a high mortality rate. Treatment options are limited and mainly consist of surgical repair at critical aortic diameters as current pharmacological interventions are unable to stop disease progression. Despite the existence of different mouse models for thoracic aortic aneurysm (TAA) and TAD, the underlying disease mechanisms remain elusive. In humans, loss-of-function of SMAD3 or SMAD6 increases the risk for TAA. We therefore targeted both ohnologs of smad3 and smad6 in zebrafish in order to further investigate their contribution to aortic homeostasis. We found an increased diameter of the ventral aorta in smad3a−/−;smad3b−/− double knockout (smad3a/b DKO) zebrafish larvae, while smad6a−/−;smad6b−/− (smad6a/b DKO) zebrafish larvae have a reduced aortic diameter. Smad3a/b DKO survive normally to adulthood, but smad6a/b DKO die before the age of 8 months due to dissections and ruptures in the ventral aorta. Smad6a/b DKO zebrafish also show hypoplasia of the aortic arches and the distal part of the ventral aorta. Surprisingly, the smad3a−/−;smad3b−/−;smad6a−/−;smad6b−/− quadruple knockout (qKO) zebrafish model has normal survival and a milder vascular phenotype compared to the smad6a/b DKO. RNA sequencing of zebrafish larvae indicates upregulation of pathways related to melanogenesis, ribosome, blood vessel development and carboxylic acid transport, and downregulation of negative regulation of endopeptidase activity and immune system. Transcriptomic data of damaged aorta compared with healthy control aorta identifies significant differences in oxidative phosphorylation, mitochondrial function, extracellular matrix and the citrate cycle. In conclusion, data from our novel zebrafish models of thoracic aortic dissection and rupture indicate that SMAD3 function has an important modifying effect on the severe aortic manifestations induced by loss of SMAD6. Legend “TAA” thoracic aortic aneurysm, “TAD” thoracic aortic dissection, “BAV” bicuspid aortic valve, “LOF” loss-of-function. Figure created with BioRender.
Pathological choroidal neovascularization underlies vision loss in neovascular age-related macular degeneration (nAMD), yet the molecular regulators coordinating vascular and immune components remain incompletely defined. Here, we investigated the role of the endolysosomal cation channel, two-pore channel 2 (TPC2) in choroidal angiogenesis. Loss of TPC2 in mice markedly reduced ex vivo choroidal sprouting, while pharmacological activation enhanced vascular growth. Mechanistically, Tpc2-deficiency led to downregulation of multiple microglia-derived pro-angiogenic factors and impaired the ability of the microglial secretome to stimulate neovascularization. In choroidal vascular cells, TPC2 loss attenuated NF-κB/MAPK signaling pathways. Tpc2-deficiency is also associated with lysosomal secretion of cathepsins, especially CTSD, resulting in decreased extracellular proteolytic activity and impaired paracrine regulation of angiogenesis. Extending these findings to human cells, TPC2 knockout in iPSC-derived endothelial cells impaired migration, tube formation, and CTSD activity in the secretome, mirroring the murine phenotype. Together, these results establish TPC2 as one of the regulators of lysosome-mediated choroidal angiogenesis, highlighting its potential as a therapeutic target in nAMD.
Post-COVID-19 syndrome is a major long-term sequela of severe SARS-CoV-2 infection, potentially involving persistent angiogenic and thromboinflammatory dysfunction, though long-term biomarker behavior remains unclear. To evaluate the evolution of angiogenic and thromboinflammatory biomarkers in post-COVID-19 syndrome patients. This ambispective cohort study was conducted at the National Institute of Respiratory Diseases in Mexico City. Thirty-two adults hospitalized for severe or critical COVID-19 in 2020 were followed for three and a half years. Paired plasma samples were collected during hospitalization and at long-term follow-up. Endothelial dysfunction markers included soluble P-selectin, vascular endothelial growth factor receptor 2, vascular endothelial growth factor D, and angiopoietin-1. Hemostasis was assessed by prothrombin time. Acute-phase proteins alpha-2-macroglobulin and haptoglobin were measured via immunoassay. Persistent symptoms were documented at follow-up. At three and a half years, persistent symptoms were common: fatigue in sixty-five point 6
Clear cell renal cell carcinoma (ccRCC), the most common renal cancer, is largely driven by von Hippel Lindau (VHL) protein deficiency. VHL inactivation promotes epithelial-to-mesenchymal transition (EMT), invasion, and hypervascularization, through vascular endothelial growth factor (VEGF) signaling, resulting in an abnormally complex vasculature. Given the limited prognostic value of microvessel density and the frequent development of resistance to VEGF-targeted therapies, the architecture of the ccRCC vascular network is likely a critical, underexplored determinant of therapeutic response. This study investigates the three-dimensional (3D) architecture of ccRCC vasculature within the tumor microenvironment and its response to drugs. Examination of human ccRCC samples revealed two vascular structures, designated ponds and sheets, that are morphologically distinct from tumor capillaries. High-resolution 3D imaging of optically cleared patient-derived xenografts revealed that ponds formed large, irregular structures with wide luminal cavity, whereas sheets were thin, elongated, and collapsed. We engineered a 3D in vitro tumor spheroid-endothelial cell co-culture model, incorporating EMT-like tumor spheroids co-cultured with endothelial cells, that mimicked pond architecture. Time-lapse imaging revealed a temporal link between tumor invasion and pond morphogenesis. Drug testing demonstrated that temsirolimus, crizotinib, and sunitinib impaired capillary morphogenesis and tumor invasion to varying extents in monoculture, while co-culture model reduced overall drug efficacy. Importantly, ponds exhibited markedly reduced sensitivity to sunitinib compared with adjacent capillaries, suggesting that they may contribute to anti-angiogenic resistance. This study defines key features and heterogeneity of ccRCC vascular architecture and highlights ponds as candidate contributors to treatment failure and targets for future interventions.
The functional and molecular definition of progenitors giving rise to blood vessel endothelium in vivo remains disputed. Upon investigating the overlap of seemingly divergent reports currently defining putative endothelial progenitor cells (EPCs) using single-cell RNA-sequencing and flow cytometry, Protein C Receptor (PROCR) and Platelet-Derived Growth Factor Receptor Alpha (PDGFRA) largely overlapped with previously characterized murine aorta’s CD34+CD31low endovascular progenitors (EVPs). Functional assays and lineage tracing in homeostatic aorta and excisional wounds demonstrated increased clonogenic capacity, engraftment potential, and ability to form differentiated endothelial (D) cells of PROCR+ PDGFRA+ EPCs, termed as refined endothelial progenitor cell (rEPC), as compared to PROCRnegPDGFRAneg EVPs. Similar PROCR and PDGFRA expression in normal human aorta, and increased clonogenic capacity of CD34+CD31lowPROCR+ endothelial cells from freshly isolated human term placenta were observed as compared to controls. Functional validation of human rEPCs is supported by PROCR enrichment, while PDGFRA co‑expression in human endothelial progenitor–like cells is supported at the transcriptomic level only. Thus, overlapping PROCR and PDGFRA expression in EVPs narrows the population with true functional progenitor capacity.
Regulator of G protein signaling 5 (RGS5) modulates G-protein coupled receptor (GPCR) signaling and is markedly upregulated in angiogenesis. However, its function in endothelial cells and its role in mediating postnatal angiogenesis remain unclear. The purpose of this study is to define the role of endothelial RGS5 in regulating VEGF signaling and angiogenesis. In a hindlimb ischemia model, we found impaired postnatal angiogenesis, reduced perfusion recovery, and increased rates of auto-amputation in mice with either global or endothelial-specific deletion of Rgs5. Rgs5 deficiency in ECs led to reduced VEGFR2 phosphorylation at Tyr1175 and its downstream signaling pathways. This was accompanied by increased activity of the tyrosine phosphatase, SHP-1, which dephosphorylates and inactivates VEGFR2. In vitro, Rgs5-deficient ECs exhibited diminished migration, increased apoptosis, and reduced viability in response to VEGF stimulation. These findings indicate that RGS5 is essential for maintaining VEGF-mediated angiogenic signaling through inhibition of SHP-1 activity. Endothelial RGS5 is a critical regulator of VEGF signaling and postnatal angiogenesis. By attenuating SHP-1–mediated dephosphorylation of VEGFR2, RGS5 preserves VEGF signaling and angiogenesis. Targeting the RGS5–SHP-1 axis may be a useful therapeutic strategy for improving angiogenesis in response to ischemia.
Quantification of retinal and avascular areas in the rat oxygen induced retinopathy (OIR) model is traditionally performed using time-intensive manual methods that may be subject to inter-rater variability. We developed and validated two open-source, semi-automated Fiji (Fiji is Just ImageJ) macros to measure total retinal area (RA) and avascular area (AA) in rat 50/10 OIR retinal flat mounts. Concordance correlation coefficients demonstrated high agreement between macro-derived and manual measurements for RA (0.988), AA (0.985), and AA/RA (0.983), with minimal bias observed. While inter-user variability was higher for macro-based AA measurements compared to manual methods, averaging results from two users improved precision. These semi-automated tools reduce analysis time and training burden while maintaining strong agreement with gold standard measurements. Although limited by user input requirements and single-laboratory validation, these macros provide accessible, standardized methods for retinal quantification and have the potential to improve reproducibility and efficiency in OIR research.
Vascular endothelial growth factor receptor-2 (VEGFR2) is a key target for regulating the endothelial cell lineage and angiogenesis. It is also expressed by lymphatic endothelial cells (LECs) while its participation in lymphangiogenesis remains inadequately characterized. We demonstrate in this study that VEGFR2 is highly expressed in dermal initial lymphatic vessels and valves. The induced deletion of pan-endothelial Vegfr2 at the neonatal stage produced a potent suppression of dermal lymphatic growth, characterized by a thinner lymphatic diameter, a decreased number of LECs and lymphatic valves. Mechanistically, VEGFR2 insufficiency led to a dramatic decrease in lymphatic VEGFR3, a key regulator mediating signals for lymphatic growth and remodeling. RNA sequencing analysis revealed that GO terms enriched for downregulated genes included biological processes related to EC development while pathways related to hematopoiesis and immune responses were upregulated in the skin of Vegfr2 mutants compared with littermate controls. This was further confirmed by RNA-seq analysis of dermal tissues 48 h after endothelial Vegfr2 deletion. Consistently, targeting Vegfr2 in PROX1+ cells produced an inhibitory effect on dermal lymphatic growth and recapitulated a similar altered transcriptomic signature. The alteration of lymphatic gene expression was further validated by siRNA-mediated Vegfr2 knockdown in primary LECs, showing a transcriptional trend toward a hematopoietic fate. Findings from this study imply that VEGFR2 is required for the maintenance of endothelial identity, and its insufficiency triggers a transcriptional reprogramming that diminishes VEGFR3-mediated lymphangiogenesis.
Hyaloid vessel regression is essential for vitreous transparency and normal vision, yet how this transient vascular network is dismantled remains unclear. Here we show that postnatal hyaloid regression in mice is not driven by a measurable increase in apoptosis, but instead by coordinated endothelial and mural cell delamination, extravascular redistribution and a transient plasticity program marked by Snail1 and Slug induction. Notch1 signalling peaks during the regression window, and vascular endothelial-specific Notch1 deletion causes persistent hyaloid vessels, with excessive proliferation and failure of endothelial and mural cell disengagement. Mechanistically, loss of Notch1 preserves endothelial identity, suppresses an endothelial-mesenchymal transition-like transcriptional program and reduces expression of the Wnt co-recepteors Lrp5 and Lrp6. Wnt pathway mutant phenocopies the delamination defect, supporting functional convergence between Notch1 and Wnt signalling during vessel involution. Together, these findings identify Notch1 as a key driver of developmental vascular pruning. They also redefine hyaloid regression as an apoptosis-non-exclusive remodelling process, with broader implications for physiological and pathological vascular remodelling, and may guide therapeutic strategies to modulate vascular regression in ocular disorders.
Despite its established role in breast cancer treatment, Doxorubicin treatment remains subject to adaptive resistance mechanisms that extend beyond cancer cell intrinsic alterations ultimately reducing therapy efficacy. Our study in a MMTV-PyMT-driven mouse breast cancer model reveals that prolonged Doxorubicin (Dox) exposure triggers significant reprogramming of the tumour vasculature, substantially altering the angiocrine landscape and shaping treatment outcomes. Notably, tumours that initially respond, but later revert, display an endothelial cell subclustering with activation of proliferative and NF-κB-dependent cytokine pathways. We further identify a novel endothelial subpopulation characterised by higher expression of drug clearance and oxidative metabolism markers, suggesting an active role in mitigating Dox efficacy and angiogenesis promotion. These findings substantiate endothelial plasticity as a critical mediator of therapeutic failure. By uncovering these vascular adaptations, our work provides a new perspective on the underlying mechanisms of Dox resistance and the prolonged efficacy of chemotherapy in breast cancer.
Vascular remodeling is crucial for establishing a functional vasculature and maintaining organ homeostasis. In the central nervous system (CNS), Wnt signaling plays a critical role in guiding endothelial cell (EC) behavior during vascular development and specialization. While canonical Wnt/β-catenin signaling regulates endothelial specification and blood–brain barrier formation, the non-canonical Wnt/Planar Cell Polarity (PCP) pathway orchestrates vascular remodeling and flow adaptation. However, how PCP signaling is transduced into intracellular polarity control remains unknown. Here, we identify MCC (Mutated in Colorectal Cancer) as a key regulator of endothelial polarity and migration downstream of the Wnt/PCP signaling pathway. Mechanistically, MCC interacts with the centriolar satellite protein CEP131 and promotes its turnover through proteasome- and autophagy-dependent pathways, thereby maintaining centrosome-associated organization required for directional polarity. MCC depletion disrupts directional polarity while preserving and enhancing flow-induced cytoskeletal elongation, revealing a functional dissociation between alignment and front–rear polarization. In vivo, endothelial-specific deletion of Mcc in the postnatal retina impairs vascular remodeling, reduces endothelial proliferation, and disrupts polarity at the angiogenic front. Notably, normalization of vascular density and regression by captopril does not restore polarity, indicating a cell-intrinsic role for MCC in endothelial organization. Together, these findings uncover an MCC–CEP131 axis linking Wnt/PCP signaling to centrosome-associated proteostasis and identify MCC as a key coordinator of endothelial polarity during vascular remodeling.
