BMP9/10-blood flow signaling crosstalk in safeguarding vessel integrity and organ functionality
Vascular disease develop often in time due to loss of the mature, quiescent endothelial cell (EC) phenotype with organ specific consequences. We have identified that canonical Bone Morphogenic Protein 9 (BMP9) signaling pathway and flow-induced shear stress act in a feedback loop to promote EC quiescence: high shear stress sensitizes ECs to BMP9 pathway activation and in turn, BMP9 signaling maintains the set-point of flow-induced EC responses. Perturbation in this fine-tuned balance leads to EC activation and permanent EC remodeling resulting in vascular dysfunction. Using in vivo and cell culture based systems in combination with transcriptomics and epigenomics approaches, the major objective of this proposal is to unravel the cellular and molecular mechanisms of organotypic EC quiescence and function regulated by the synergy of angiocrine BMP9/10-Smad4 and shear stress. Ultimately, we aim to identify novel angiocrine signals as promising therapeutic approaches for vascular dysfunction.