title: Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia.
abstract: BACKGROUND
  Vascular maturation plays an important role in wound repair post-myocardial infarction (MI). The Notch3 is critical for pericyte recruitment and vascular maturation during embryonic development.
  
  
  OBJECTIVE
  This study is to test whether Notch3 deficiency impairs vascular maturation and blunts cardiac functional recovery post-MI.
  
  
  RESULTS
  Wild type (WT) and Notch3 knockout (Notch3KO) mice were subjected to MI by the ligation of left anterior descending coronary artery (LAD). Cardiac function and coronary blood flow reserve (CFR) were measured by echocardiography. The expression of angiogenic growth factor, pericyte/capillary coverage and arteriolar formation were analyzed. Loss of Notch3 in mice resulted in a significant reduction of pericytes and small arterioles. Notch3 KO mice had impaired pericyte/capillary coverage and CFR compared to WT mice. Notch3 KO mice were more prone to ischemic injury with larger infarcted size and higher rates of mortality. The expression of CXCR-4 and VEGF/Ang-1 was significantly decreased in Notch3 KO mice. Notch3 KO mice also had few NG2+/Sca1+and NG2+/c-kit+progenitor cells in the ischemic area and exhibited worse cardiac function recovery at 2weeks after MI. These were accompanied by a significant reduction of pericyte/capillary coverage and arteriolar maturation. Furthermore, Notch3 KO mice subjected to MI had increased intracellular adhesion molecule-2 (ICAM-2) expression and CD11b+macrophage infiltration into ischemic areas compared to that of WT mice.
  
  
  CONCLUSIONS
  Notch3 mutation impairs recovery of cardiac function post-MI by the mechanisms involving the pre-existing coronary microvascular dysfunction conditions, and impairment of pericyte/progenitor cell recruitment and microvascular maturation.
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA; Emergency Department of China-Japan Friendship Hospital, Beijing 100029, China.
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Tao
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Heng
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Emergency Department of China-Japan Friendship Hospital, Beijing 100029, China. Electronic address: zhangchong2003@vip.sina.com.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Zhang
authors.affiliation: Duke University School of Medicine, Durham, USA.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Hunan University of Chinese Medicine, Changsha, Hunan 410208, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wen
authors.affiliation: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA; Hunan University of Chinese Medicine, Changsha, Hunan 410208, China. Electronic address: JChen3@umc.edu.
authors.forename: Jian-Xiong
authors.initials: JX
authors.lastname: Chen
mesh_terms: D000818:Animals; D003326:Coronary Circulation / Q000502:physiology*; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000071656:Receptor, Notch3 / Q000172:deficiency*; D020127:Recovery of Function / Q000502:physiology*
chemical_list: C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3
keywords: Myocardial infarction; Notch3 deficiency; Pericytes; Vascular maturation; Vascular progenitor cells