RASA1-dependent cellular export of collagen IV controls blood and lymphatic vascular development. J Clin Invest 2019 Jun 11;129(9):3545-3561
Date
06/12/2019Pubmed ID
31185000Pubmed Central ID
PMC6715364DOI
10.1172/JCI124917Scopus ID
2-s2.0-85067800404 (requires institutional sign-in at Scopus site) 37 CitationsAbstract
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.
Author List
Chen D, Teng JM, North PE, Lapinski PE, King PDAuthor
Paula E. North MD, PhD Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAnimals, Newborn
Apoptosis
Arteriovenous Malformations
Cell Line, Tumor
Collagen Type IV
Edema
Endoplasmic Reticulum
Female
Heart Valves
Heart Ventricles
Hemorrhage
Lymphatic Vessels
MAP Kinase Signaling System
Mice
Mice, Inbred C57BL
Neoplasm Transplantation
Neovascularization, Pathologic
Phenotype
Phenylbutyrates
Pregnancy
Signal Transduction
Transgenes
p120 GTPase Activating Protein
