Abstract Body: Vascular smooth muscle cells (SMCs) are central to cardiovascular diseases including atherosclerosis and intimal hyperplasia. In these pathologies, SMCs de-differentiate to “synthetic” phenotypes and acquire invasive, proliferative, fibrotic, and inflammatory properties. We investigated whether the primary cilia, a receptor-rich organelle regulating signaling and cell cycle entry, influences SMC phenotypic switching. Our data suggests that IFT88, a key cilia gene, is significantly upregulated in human coronary artery SMCs upon serum starvation or treatment with pro-differentiation agent rapamycin. Confocal microscopy revealed that siRNA-mediated IFT88 knockdown dramatically reduced primary cilia formation in vitro. IFT88 silencing decreased contractile gene expression (ACTA2, MYH11, TAGLN) and contractility and increased synthetic genes (KLF4, SPP1). IFT88-deficient SMCs also exhibited significantly reduced invasion, motility, and proliferation in vitro, suggesting that cilia may be required for differentiated SMC to responds to growth factors. Notably, siIFT88 knockdown significantly decreased the SMC signaling and dedifferentiation response to PDGF-BB signaling in vitro according to western blotting and qPCR. Using tissue clearing and immunofluorescent labeling, we noted that approximately 30% of SMCs are ciliated in normal human and mouse aortas. Human thoracic aorta scRNAseq data revealed that a sub-population of SMC expresses high levels of IFT88, and these SMCs express higher levels of contractile genes and growth factor receptors (PDGFRA, BMPR). In a mouse carotid artery ligation model of intimal hyperplasia, immunostaining for IFT88 revealed increased medial ciliation proximal to internal elastic lamina at 7 days post injury (dpi), and prominent neointimal ciliation at 21 dpi. ScRNAseq data further suggest that high SMC Ift88 expression correlates with mitotic and chemotactic gene expression during early remodeling (3 dpi) compared to Ift88 low SMCs. We have generated a novel SMC-specific Ift88 knockout mouse strain with lineage tracing and are testing whether the IFT88-high ciliated subpopulation drives clonal neointima formation. Our data suggest that IFT88 promotes the contractile phenotype and growth factor responses, and that ciliated SMCs represent a novel contractile subpopulation that are geographically and functionally primed to promote intimal hyperplasia.