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 (ECs) 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 ECs 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 ECs and deposition in vascular basement membranes. In the absence of RASA1, dysregulated Ras/MAPK signal transduction in ECs 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 for a better understanding of the molecular pathogenesis of CM-AVM and possible means of treatment.
Di Chen, Joyce M. Teng, Paula E. North, Philip E. Lapinski, Philip D. King
Usage data is cumulative from June 2019 through February 2020.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.