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Enhanced matrix metalloproteinases-2 activates aortic endothelial hypermeability, apoptosis and vascular rarefaction
1Institute of Microcirculation, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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.
Insights
Matrix metalloproteinase-2 (MMP-2) contributes to microvascular rarefaction in spontaneously hypertensive rats by cleaving key proteins. Doxycycline inhibits MMP-2, protecting endothelial cells and preventing apoptosis.
Area of Science:
- Cardiovascular Biology
- Endothelial Cell Biology
- Hypertension Research
Background:
- Microvascular rarefaction and endothelial cell apoptosis are hallmarks of hypertensive complications.
- Elevated matrix metalloproteinase (MMP) activity is observed in hypertensive rat models, but its precise role in rarefaction is unclear.
- Existing research suggests MMPs cleave VEGFR2, but their impact on Beta-Catenin and VE-cadherin in this context requires further investigation.
Purpose of the Study:
- To investigate the mechanisms underlying microvascular rarefaction in spontaneously hypertensive rats (SHR).
- To determine the role of matrix metalloproteinases (MMPs), specifically MMP-2, in endothelial cell apoptosis and rarefaction.
- To test the hypothesis that MMP-mediated cleavage of Beta-Catenin and VE-cadherin contributes to endothelial cell apoptosis and rarefaction.
Main Methods:
- Primary rat aortic endothelial cells (RAECs) were isolated and utilized in an in-vitro model.
- Transwell systems assessed endothelial cell permeability.
- Immunofluorescence and Western blotting analyzed endothelial adhesion molecules; MMP-2 activity was measured.
Main Results:
- Spontaneously hypertensive rat RAECs exhibited significantly increased MMP-2 activity and hyper-permeability compared to controls.
- Doxycycline treatment (50 μM) reduced MMP-2 levels, attenuated hyper-permeability, and protected VEGFR2, VE-cadherin, and Beta-catenin from cleavage.
- Doxycycline prevented the reduction of mitochondrial transmembrane potential (MTP) and subsequent mitochondria-mediated apoptotic signaling.
Conclusions:
- MMP-2 activity plays a critical role in the microvascular rarefaction of spontaneously hypertensive rats, independent of blood pressure.
- MMP-2 contributes to endothelial cell apoptosis by cleaving VEGFR2, VE-cadherin, and Beta-catenin, leading to capillary rarefaction.
- Doxycycline demonstrates a protective effect by inhibiting MMP-2, preserving endothelial cell integrity, and preventing apoptosis.
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