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Abstract

Arterial-venous malformations (AVMs) are direct connections between arteries and veins with a missing capillary bed that lacks pericytes (PCs). Recent studies have highlighted the significance of PCs and their recruitment in maintaining vascular integrity. Whether impaired PC coverage triggers AVMs or is secondary to hemodynamics changes in high-flow AVMs remains unclear. Among a plethora of regulators, PDGFB signaling has emerged as a key pathway involved in PC recruitment to the endothelial cells (ECs). The aim of my study was to i) investigate the effects of the BMP9/10 - flow signaling pathway crosstalk on PDGFB-mediated PC biology and function and ii) elucidate the role of endothelial PDGFB-mediated PC recruitment and maintenance in the pathogenesis of AVMs. Consistent with previous findings identifying loss of PCs on the AVM endothelium, this study identified a specific loss of PDGFRβ in the remaining PCs, indicating dysfunctional PDGFB signaling as the responsible mechanism for the PC deficit. Further in vitro studies confirmed this hypothesis, as PDGFB was synergistically upregulated by BMP9 and fluid shear stress and this effect was SMAD4 dependent. Cellularly, SMAD4 was required for PDGFB-mediated PC migration in vitro. Endothelial specific Pdgfb depleted mouse line (Pdgfbi∆EC) was generated for in vivo experiments to determine whether disrupted EC-PC crosstalk contributes to AVM formation. Interestingly, disruption of EC Pdgfb-mediated PC loss and maintenance leads to AVM-like structures. In addition, endothelial PDGFB signaling-mediated PC recruitment is required to maintain capillary EC size and diameter, cell fate, arterial-venous identity and EC migration against the bloodstream to promote appropriate vascular tone and stability of vessels and protect against AVM formation. Mechanistically, I identified that PDGFB protects the developing endothelium against hemodynamics changes by restricting KLF4-mediated NOTCH, BMP and TGF-β activation in ECs. Taken together, these results suggest that SMAD4-flow synergy modulate the PDGFB signaling mediated PC recruitment and maintenance to maintain EC quiescence. Targeting SMAD4-PDGFB signaling may be a potential therapeutic approach to prevent AVM formation by restoring and enhancing PC recruitment and maintenance.