title: Enhanced matrix metalloproteinases-2 activates aortic endothelial hypermeability, apoptosis and vascular rarefaction in spontaneously hypertensive rat.
abstract: Microvascular rarefaction with endothelial cells apoptosis is a common characteristic of various microvascular complications in the spontaneously hypertensive rat (SHR). Elevated levels of proteolytic (e.g. matrix metalloproteinase, MMPs) activity and apoptosis in aortic endothelial cells of SHR were found when compared to its normotensive control. However, the exact mechanisms of microvascular rarefaction and the role of MMPs in this process remain poorly understood. Besides cleavage of VEGFR2 via unbalanced MMPs, we hypothesize that selected cleavage of Beta-Catenin and VE-cadherin by MMPs could induce apoptosis of rat aortic endothelial cells (RAECs) and rarefaction. Primary RAECs were isolated, identified and used in a in-vitro model. Transwell system was used to analyze the permeability of Wistar RAECs, SHR RAECs and SHR RAECs with pretreatment by doxycycline. Qualitative and semi-quantitative analysis of major endothelial adhesion molecules were detected by immunofluorescence technique and Western blot, respectively. MMP-2 activity of SHR RAECs was increased significantly and doxycycline (50 μM) effectively reduced the level of MMP-2 and hyper-permeability in SHR RAECs. SHR RAECs showed enhanced cleavage of VEGFR2, VE-cadherin and B-catenin, which could be prevented by doxycycline (50 μM). Doxycycline (50 μM) attenuated hyper-permeability via decreased MMP-2 by protecting VEGFR2, VE-cadherin, Beta-catenin from cleavage and inhibited the reduction of mitochondrial transmembrane potential (MTP), thus prevented mitochondria-mediated apoptotic signaling and capillary rarefaction in the SHR. It might be a novel insight into the mechanisms of SHR microvascular rarefaction that is independent of pressure but relevant to MMP-2.
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: B W
authors.initials: BW
authors.lastname: Li
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: H W
authors.initials: HW
authors.lastname: Li
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: A L
authors.initials: AL
authors.lastname: Li
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: X C
authors.initials: XC
authors.lastname: Yuan
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: R J
authors.initials: RJ
authors.lastname: Xiu
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001011:Aorta / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D017209:Apoptosis; D002478:Cells, Cultured; D004318:Doxycycline / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006973:Hypertension / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D051176:beta Catenin; D040301:Vascular Endothelial Growth Factor Receptor-2; D020778:Matrix Metalloproteinase 2; D004318:Doxycycline
keywords: Beta-catenin; MMP-2; SHR; VE-cadherin; aortic endothelial cells; hypermeability; microvascular rarefaction