FBLN7 mediates vascular smooth muscle cell phenotype switching and vascular remodeling in hypertension

<b>Rationale:</b> Arterial remodeling serves as a pivotal mechanism underlying the development of diseases such as hypertension. Fibulin-7 (FBLN7), an adhesion protein, remains enigmatic regarding its role in these pathological processes. This study aims to explore whether FBLN7 influences vascular remodeling and its underlying mechanisms. <b>Methods:</b> We generated FBLN7 knockout mice and smooth muscle-specific FBLN7 overexpression mice. Vascular remodeling models were established by administering angiotensin II (Ang II) for 28 days. RNA sequencing, western blot, and immunofluorescence assays were employed to investigate the biological function of FBLN7 in vascular smooth muscle cells (VSMCs). The interaction mechanism between FBLN7 and cell membrane receptors was explored through mass spectrometry analysis, co-immunoprecipitation techniques and molecular dynamics simulations. <b>Results:</b> Bioinformatics analysis revealed an upregulation of FBLN7 expression in the vascular remodeling model, with FBLN7 predominantly localized in VSMCs. Subsequent <i>in vivo</i> validation demonstrated that FBLN7 knockout attenuated Ang II-induced vascular remodeling, reducing aortic wall thickness and collagen formation. Conversely, VSMC-specific overexpression of FBLN7 via AAV vectors exacerbating the remodeling phenotype. Functionally speaking, FBLN7 potentiates Ang II-mediated phenotypic transformation. Mechanistically, FBLN7 interacts with the extracellular and transmembrane domains of syndecan-4 (SDC4) via its C-terminal region, affecting SDC4 signaling and dimer formation. This interaction inhibits SDC4-mediated activation of the Rho-associated protein kinase pathway, subsequently reducing nuclear translocation of myocardin-related transcription factor A, leading to decreased transcription of genes associated with the contractile VSMCs phenotype. <b>Conclusions:</b> These findings reveal FBLN7 promotes the transition of VSMCs from a contractile to a synthetic phenotype, thereby aggravating vascular remodeling. This provides further insights into the pathogenesis of vascular remodeling and potential therapeutic strategies.