Brain vascular stability relies on PAK2–cilia–PDGF-BB–HSPGs on basolateral side of endothelium

Endothelial cells (ECs) in the brain communicate with mural cells to facilitate vascular stability. Platelet-derived growth factor-BB (PDGF-BB)/platelet-derived growth factor receptor-β (PDGFR-β) signaling mechanism at EC-mural cell interface helps stabilize the vasculature. How this paracrine signaling is mediated is not known. Our laboratory studies endothelial cilia, a microtubule-based organelle, and its role in promoting vascular stability. We discovered that brain endothelial cilia are located primarily on the basolateral side, and PDGF-BB is expressed in EC cilium. Thus, we hypothesized that endothelium cilium in conjunction with PDGF-BB on the basolateral side is responsible for mural cell recruitment. In this study, using a combination of zebrafish, mice, and human brain model systems, we have established a signaling paradigm wherein p21-activated kinase (PAK2) and ADP-ribosylation factor-13b (ARL13b) in ECs induce secretion of PDGF-BB. PDGF-BB associates with heparan sulfate proteoglycans (HSPGs) to form a gradient around ECs. Disrupting PAK2 affects ciliogenesis, HSPGs, and PDGF-BB gradient. We unravel a new mechanism involving endothelial cilia/PAK2-mediated PDGF-BB secretion, and retention by periendothelial HSPGs to promote vascular stability via recruiting mural cells.