1. RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development
- Author
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Philip E. Lapinski, Joyce M.C. Teng, Philip D. King, Di Chen, and Paula E. North
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Collagen Type IV ,Angiogenesis ,MAP Kinase Signaling System ,Heart Ventricles ,Apoptosis ,Hemorrhage ,Endoplasmic Reticulum ,Arteriovenous Malformations ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pregnancy ,Cell Line, Tumor ,Animals ,Edema ,Transgenes ,Protein kinase A ,Lymphatic Vessels ,Neovascularization, Pathologic ,Chemistry ,Endoplasmic reticulum ,ER retention ,p120 GTPase Activating Protein ,General Medicine ,Heart Valves ,Phenylbutyrates ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Phenotype ,Ras Signaling Pathway ,Animals, Newborn ,030220 oncology & carcinogenesis ,Vascular Disorder ,Female ,Signal transduction ,Neoplasm Transplantation ,Signal Transduction ,Research Article - Abstract
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.
- Published
- 2019