PINCH proteins orchestrate vascular mural cell homeostasis through integrated signaling and transcriptional networks.

Vascular mural cells (VMCs) are crucial for vascular stability, and their dysfunction underlies cardiovascular pathologies including atherosclerosis and aortic aneurysms. PINCH proteins are core focal adhesion components mediating integrin signaling, yet their roles in VMC development remain elusive. Here, we generated mice with conditional deletion of both PINCH1 and PINCH2 in Pdgfrb-lineage VMCs, which resulted in perinatal lethality accompanied by severe arterial enlargement, hemorrhage and defective angiogenesis. Mutant VMCs exhibited profound defects in cytoskeletal organization, proliferation, differentiation, adhesion and extracellular matrix assembly. Multi-omics analyses revealed that PINCH deficiency dysregulated phospho-signaling networks, hyperactivating PDGFR/EGFR/AKT/ERK and STAT/NF-κB pathways while impairing integrin-FAK-SRC and cell cycle-associated pathways (p53, p27). RNA-seq demonstrated altered expression of genes enriched in immune response (CD74, Tlr2), cytoskeleton (TUBB3, ACTA2) and VMC differentiation (Rgs5, Kcnj8, ABCC9). Importantly, we identified PINCH1 as a nuclear transcriptional coregulator that directly represses proliferative-inflammatory programs while promoting contractile-adhesive and cytoskeletal organization signatures. The clinical relevance of these findings is underscored by downregulation of PINCH genes in human atherosclerosis and Marfan syndrome aneurysms, with conserved dysregulation of key PINCH targets including CD74 and RGS5. Our work reveals a dual cytoplasmic-nuclear mechanism for PINCH in maintaining vascular homeostasis, providing both mechanistic insights and therapeutic targets for vascular diseases.