Bone Morphogenetic Protein signaling in the endothelium

Abstract

Endothelial cells (ECs), the lining of blood vessels, exhibit remarkable diversity. This heterogeneity plays a crucial role in how these cells distinctively respond to signals that control their proliferation during angiogenesis.1-3 Previous research suggests that proliferative capacity (ability to proliferate in response to stimuli), a critical factor determining the extent of angiogenesis, varies in different EC subtypes, such as arterial and venous ECs.1,4 However, the specific molecules that define this proliferative capacity based on EC subtype remained largely unknown. This study delves into the role of Bone Morphogenetic Protein (BMP) signaling in ECs. We found that BMP signaling preferentially promoted proliferation in venous ECs compared to their arterial counterparts. Further analysis using techniques including single-cell RNA sequencing identified two key players: ALK1 and ALK2, endothelial-enriched type I BMP receptors. Interestingly, these receptors appeared to have opposing roles in angiogenesis, with ALK1 acting as an inhibitor,5-7 and ALK2 promoting proliferation. In the process, ALK2 might enable venous endothelium to maintain its high proliferative potential by suppressing the expression of CDKN1A/p21, a cell cycle inhibitor.8,9 Furthermore, ALK2 appeared to modulate ALK1 activity through the formation of ALK1-ALK2 hetero-dimers. These results suggest that in venous ECs, ALK2 plays a crucial role in determining their angiogenic potential by influencing both CDKN1A/p21 expression and ALK1 activity. Our research could offer valuable insights into how BMP regulates blood vessel formation in a context dependent manner. Understanding this mechanism could pave the way for the development of novel therapeutic strategies targeting specific EC subtypes for promoting healthy vascular growth or inhibiting uncontrolled angiogenesis in diseases.