Defining the functional influence of endothelial cell-expressed oncogenic activating mutations on vascular morphogenesis and capillary assembly

Am J Pathol. 2023 Oct 12:S0002-9440(23)00375-9. doi: 10.1016/j.ajpath.2023.08.017. Online ahead of print.ABSTRACTWe sought to define key molecules and signals controlling major steps in vascular morphogenesis, and how these signals regulate pericyte recruitment and pericyte-induced basement membrane deposition. The morphogenic impact of EC expression of activating mutants of kRas, Mek1, PIK3CA, Akt1, Rheb, Jak2, or Stat3 expression vs. controls was evaluated, along with EC signaling events, pharmacological inhibitor assays, and siRNA suppression experiments. We observe that primary stimulators of EC lumen formation include kRas, Akt1, and Mek1, while PIK3CA and Akt1 stimulate a specialized type of cystic lumen formation. In contrast, the key drivers of EC sprouting behavior are Jak2, Stat3, Mek1, PIK3CA, and Rheb (mTOR). These conclusions are further supported by pharmacological inhibitor and siRNA suppression experiments. EC expression of active Akt1, kRas, and PIK3CA led to markedly dysregulated lumen formation coupled to strongly inhibited pericyte recruitment and basement membrane deposition. For example, activated Akt1 expression in ECs excessively stimulates lumen formation, decreases EC sprouting behavior, and show minimal pericyte recruitment with reduced mRNA expression of PDGF-BB, PDGF-DD, and endothelin-1; critical EC-derived factors known to stimulate pericyte invasion. We identify key signals controlling fundamental steps in capillary morphogenesis and maturation...

Source: Am J Pathol - October 14, 2023 Category: Pathology Authors: Prisca K Lin Zheying Sun George E Davis Source Type: research