RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development.
Combined germline and somatic second hit inactivating mutations of the RASA1 gene, which encodes a negative regulator of the Ras signaling pathway, cause blood and lymphatic vascular lesions in the human autosomal dominant vascular disorder capillary malformation-arteriovenous malformation (CM-AVM). How RASA1 mutations in endothelial cells (EC) result in vascular lesions in CM-AVM is unknown. Here, using different murine models of RASA1-deficiency, we found that RASA1 was essential for the survival of EC during developmental angiogenesis in which primitive vascular plexuses are remodeled into hierarchical vascular networks. RASA1 was required for EC survival during developmental angiogenesis because it was necessary for export of collagen IV from EC and deposition in vascular basement membranes. In the absence of RASA1, dysregulated Ras mitogen-activated protein kinase (MAPK) signal transduction in EC resulted in impaired folding of collagen IV and its retention in the endoplasmic reticulum (ER) leading to EC death. Remarkably, the chemical chaperone, 4-phenylbutyric acid, and small molecule inhibitors of MAPK and 2-oxoglutarate dependent collagen IV modifying enzymes rescued ER retention of collagen IV and EC apoptosis and resulted in normal developmental angiogenesis. These findings have important implications with regards an understanding of the molecular pathogenesis of CM-AVM and possible means of treatment.
['Chen|Di|D|', 'Teng|Joyce M|JM|', 'North|Paula E|PE|', 'Lapinski|Philip E|PE|', 'King|Philip D|PD|']
D000818:Animals D000831:Animals, Newborn D017209:Apoptosis D001165:Arteriovenous Malformations D045744:Cell Line, Tumor D024141:Collagen Type IV D004487:Edema D004721:Endoplasmic Reticulum D005260:Female D006351:Heart Valves D006352:Heart Ventricles D006470:Hemorrhage D042601:Lymphatic Vessels D020935:MAP Kinase Signaling System D051379:Mice D008810:Mice, Inbred C57BL D009368:Neoplasm Transplantation D009389:Neovascularization, Pathologic D010641:Phenotype D010654:Phenylbutyrates D011247:Pregnancy D015398:Signal Transduction D019076:Transgenes D020729:p120 GTPase Activating Protein
endothelial cells Angiogenesis Molecular pathology Mouse models Vascular Biology