Abstract 17153: Smooth Muscle Cells Regulate the Capacity for Endothelial Regeneration by Coordinating Notch1 Mediated Metabolism, Histone Acetylation and Gene Regulation in a BMPR2 Dependent Manner
Maintaining endothelial cells (EC) as a monolayer in the vessel wall, depends on a profile of gene expression and on the metabolic state, features influenced by contact with cells such as pericytes and smooth muscle cells (SMC). Dysregulation of BMP receptor 2 (BMPR2) signaling disrupts pulmonary artery (PA) EC metabolism and monolayer formation and is associated with vascular diseases such as pulmonary arterial hypertension. Here we show that BMPR2 signaling in either EC or SMC is required to maintain contact-dependent production of collagen IV, triggering integrin linked kinase to target p-JNK to caveolin1, and activate γ-secretase. Notch1 activation by the γ-secretase produces the Notch1 intracellular domain (N1ICD) that is responsible for increasing glycolysis, mitochondrial mass, and oxidative phosphorylation in association with an increase in the enzyme, 6-phosphofructo-2-kinase (PFKFB3). The increase in PFKFB3 is responsible for elevated levels of the mitochondrial citrate transporter that generates acetyl CoA and for heightened acetylation of histones H3K27 and H3K9. The latter are associated with the transcription of N1ICD target genes Hey1, HES1 and c-Myc, and for the Hey1/HES1 mediated repression of migratory genes Neuropilin1 and 2. This maintains the Notch1-dependent ‘stalk cell’ phenotype that retains the capacity to proliferate but not migrate. As a result there is rapid re-endothelialization of the PAEC monolayer in a scratch wound healing assay that is impaired with loss of BMPR2 in both PAEC and PASMC in contact co-cultures. Consistent with this, a mouse heterozygous knockout for BMPR2 has impaired re-endothelialization following wire injury of the carotid artery and neointimal formation is greatly enhanced. Taken together our data provide novel evidence for the role of BMPR2 in EC and SMC myoendothelial junctions in maintaining the proliferative capacity of EC in response to injury and thereby in limiting occlusive changes (Figure A and B).
Author Disclosures: K. Miyagawa: None. J.K. Hennigs: None. C.G. Li: None. P. Chen: None. M. Wang: None. S. Taylor: None. S. Sa: None. A. Cao: None. L. Wang: None. M. Rabinovitch: None.
- © 2016 by American Heart Association, Inc.