TMEM215 is an endoplasmic reticulum-localized, two-pass transmembrane protein that functions primarily as a pro-survival factor for endothelial cells (ECs) during angiogenesis and vessel remodeling 1. Mechanistically, TMEM215 prevents EC apoptosis by binding the chaperone BiP and facilitating its interaction with the pro-apoptotic protein BIK, thereby blocking BIK-regulated mitochondrial calcium influx through ER-mitochondrial membranes 2. TMEM215 expression in ECs is induced by laminar shear stress via EZH2 downregulation 2. Loss of TMEM215 impairs sprouting angiogenesis in vitro and developmental retinal vasculature in vivo, characterized by reduced lumen formation and abnormal vessel development 1. In pathological contexts, EC-specific TMEM215 depletion inhibits tumor angiogenesis and lung metastasis, indicating potential therapeutic value in cancer 2. Notably, reduced TMEM215 expression associates with less aggressive colorectal cancer phenotypes, while a chromosome 9 SNP near TMEM215 shows association with visceral leishmaniasis susceptibility 34. TMEM215 may also participate in protein-protein interaction networks through PDZ domain interactions 5. These findings position TMEM215 as a critical regulator of EC survival during both developmental and pathological angiogenesis.