By Megan Mayerle, PhD

July 2, 2019

Dysfunctional endothelial cells (ECs) are related to many cardiovascular diseases, including atherosclerosis and pulmonary arterial hypertension. Endothelial cells’ ability to properly regenerate is necessary to prevent progressive cardiovascular disease. Blockages can form in arteries and veins when ECs don’t properly regenerate into a thin monolayer lining the interior of the blood vessel.  This monolayer is anti-inflammatory and produces factors important in vessel dilation and in preventing smooth muscle cell proliferation.

The molecules BMPR2 and Notch1 are both required for angiogenesis, but little is known about how they interact to coordinate EC metabolism, chromatin remodeling and gene regulation in order to regulate EC proliferation, and monolayer regeneration.

A team of Stanford researchers led by Drs. Kazuya Miyagawa and Marlene Rabinovitch have recently published a paper in Circulation Research that answers some of these questions.

The team discovered that physical contact between smooth muscle cells and endothelial cells in blood vessels is required for BMPR2-mediated activation of Notch signaling. Notch signaling in turn leads to changes in EC metabolism and gene expression that promote ECs’ ability to regenerate. Using a molecular approach, Miyagawa and colleagues found that Notch1 stimulated ECs to make more mitochondria, subcellular structures that produce most of the power cells need to function. In addition, they showed that Notch1 induced metabolic changes to remodel chromatin at particular sites that Notch targeted to activate expression of a number of genes known stimulate cell proliferation.  

The scientists also used a mouse model of pulmonary hypertension to study how Notch1 functions after injury. They found that the ECs of mutant mice who didn’t make enough BMPR2 didn’t have as much Notch1 signaling, were less proliferative, and that the linings of their blood vessels did not reform correctly after injury. Deleting Notch1 in the endothelial cells of transgenic mice led to worsening of pulmonary hypertension.  Taken together the study suggested that activating Notch1 in ECs might be a promising therapeutic strategy in pulmonary and systemic vascular diseases like atherosclerosis and pulmonary arterial hypertension.

Stanford scientists Minyi Shi, Pin-I Chen, Jan K. Hennigs, Zhixin Zhao, Mouer Wang, Caiyun G. Li, Toshie Saito, Shalina Taylor, Silin Sa, Aiqin Cao, Lingli Wang, and Michael P. Snyder also contributed. This work was supported by National Institutes of Health, National

Heart, Lung, and Blood Institute (NHLBI) grants R01 HL087118 and R01 HL074186 to M. Rabinovitch. K. Miyagawa was supported by fellowships from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad and The Uehara Memorial Foundation and J.K. Hennigs was supported by a fellowship from the German Research Foundation (He 6855/1-1). M. Rabinovitch is supported in part by the Dunlevie Chair in Pediatric Cardiology at Stanford University.