Journal
ANGIOGENESIS
Volume -, Issue -, Pages -Publisher
SPRINGER
DOI: 10.1007/s10456-023-09900-w
Keywords
Pericytes; PDGFB; AVMs; EC migration; Arterial-venous zonation
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This study investigates the role of PDGFB in AVM pathogenesis. The results show that disruption of EC Pdgfb-mediated PC recruitment and maintenance leads to capillary enlargement and AVM-like structures. Mechanistically, PDGFB maintains capillary EC size and caliber, limiting hemodynamic changes and regulating EC signaling activation. This study suggests that inducing or activating PDGFB signaling may be a viable therapeutic approach for treating vascular malformations.
Arterial-venous malformations (AVMs) are direct connections between arteries and veins without an intervening capillary bed. Either familial inherited or sporadically occurring, localized pericytes (PCs) drop is among the AVMs' hallmarks. Whether impaired PC coverage triggers AVMs or it is a secondary event is unclear. Here we evaluated the role of the master regulator of PC recruitment, Platelet derived growth factor B (PDGFB) in AVM pathogenesis. Using tamoxifen-inducible deletion of Pdgfb in endothelial cells (ECs), we show that disruption of EC Pdgfb-mediated PC recruitment and maintenance leads to capillary enlargement and organotypic AVM-like structures. These vascular lesions contain non-proliferative hyperplastic, hypertrophic and miss-oriented capillary ECs with an altered capillary EC fate identity. Mechanistically, we propose that PDGFB maintains capillary EC size and caliber to limit hemodynamic changes, thus restricting expression of Kruppel like factor 4 and activation of Bone morphogenic protein, Transforming growth factor beta and NOTCH signaling in ECs. Furthermore, our study emphasizes that inducing or activating PDGFB signaling may be a viable therapeutic approach for treating vascular malformations.
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