Circ Res. 2026 Jun 19;139(1):e327266. doi: 10.1161/CIRCRESAHA.125.327266. Epub 2026 Jun 18.
ABSTRACT
PC1 (polycystin-1), traditionally viewed through the lens of renal pathophysiology in autosomal dominant polycystic kidney disease, has emerged as a central regulator of cardiovascular mechanobiology. Recent structural elucidation of the PC1/PC2 (polycystin-2) complex provides a molecular framework emphasizing its mechanically sensitive ectodomain, regulated proteolytic cleavage, and functional coupling with PC2, framing PC1 as a versatile integrator of biomechanical cues, extracellular matrix interactions, and Ca2+ signaling across cardiovascular cell types. This review synthesizes evidence demonstrating that PC1 plays a direct and primary role in the cardiovascular system, independent of renal decline, regulating vascular homeostasis, endothelial shear stress responsiveness, smooth muscle phenotype, and myocardial mechanotransduction. We describe the molecular mechanisms whereby PC1 dysfunction perturbs nitric oxide signaling, cytoskeletal remodeling, excitation-contraction coupling, and hypertrophic transcriptional programs, and highlight tissue-specific roles in cardiac morphogenesis and adult myocardial integrity. By integrating structural biology with cardiovascular physiology, this review provides a unified framework for understanding PC1 as a master mechanosensor linking biomechanical forces to pathological remodeling. Critical knowledge gaps, emerging therapeutic opportunities, and the potential role of artificial intelligence in PC1-targeted drug discovery are also discussed.
PMID:42313903 | DOI:10.1161/CIRCRESAHA.125.327266