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Updated: Jun 3, 2026
Rat Mesentery Exteriorization: A Model for Investigating the Cellular Dynamics Involved in Angiogenesis
Published on: May 20, 2012
Matrix metalloproteinase activity causes VEGFR-2 cleavage and microvascular rarefaction in rat mesentery
Edward D Tran1, Ming Yang, Andrew Chen
1Department of Bioengineering, The Whitaker Institute for Biomedical Engineering, University of California San Diego, La Jolla, California 92093-0412, USA.
Abstract:
A complication of the spontaneously hypertensive rat (SHR) is microvascular rarefaction, defined by the loss of microvessels. However, the molecular mechanisms involved in this process remain incompletely identified. Recent work in our laboratory suggests that matrix metalloproteinases (MMPs) may play a role by cleavage of the vascular endothelial growth factor receptor 2 (VEGFR-2). In order to further delineate the role for MMPs in microvascular rarefaction, the objective of the current study was to examine the relationship in the same tissue between MMP activity, VEGFR-2 cleavage and rarefaction. Using an in vivo microzymographic technique, we show significantly enhanced levels of MMP-1, -1/-9, -7, and -8 activities, but not MMP-2 and -3 activities, along mesenteric microvessels of the SHR compared to its normotensive control, Wistar Kyoto rat. Based on immunohistochemical methods, the SHR exhibited a decreased labeling of the extracellular, but not the intracellular, domain of VEGFR-2 along mesenteric microvessels. Chronic MMP inhibition served to attenuate VEGFR-2 cleavage and microvascular network rarefaction in the SHR mesentery. These results spatially link MMP-induced VEGFR-2 cleavage and rarefaction in the mesentery of the SHR and thus support the hypothesis that MMPs serve as regulators of microvascular dysfunction in hypertension.
Insights
Matrix metalloproteinases (MMPs) contribute to microvascular rarefaction in hypertensive rats by cleaving vascular endothelial growth factor receptor 2 (VEGFR-2). Inhibiting MMPs reduced this cleavage and rarefaction, highlighting MMPs
Area of Science:
- Cardiovascular Biology
- Hypertension Research
- Molecular Medicine
Background:
- Hypertension is linked to microvascular rarefaction, a loss of small blood vessels.
- The precise molecular mechanisms driving this rarefaction are not fully understood.
- Matrix metalloproteinases (MMPs) are implicated, potentially through vascular endothelial growth factor receptor 2 (VEGFR-2) cleavage.
Purpose of the Study:
- To investigate the relationship between MMP activity, VEGFR-2 cleavage, and microvascular rarefaction in spontaneously hypertensive rats (SHR).
- To determine if MMP inhibition can mitigate VEGFR-2 cleavage and rarefaction in the SHR mesentery.
Main Methods:
- In vivo microzymography to measure MMP activity in mesenteric microvessels of SHR and Wistar Kyoto rats.
- Immunohistochemistry to assess VEGFR-2 extracellular and intracellular domain labeling.
- Chronic MMP inhibition to evaluate its effects on VEGFR-2 cleavage and rarefaction.
Main Results:
- Elevated MMP-1, -1/-9, -7, and -8 activity observed in SHR mesenteric microvessels compared to controls.
- Reduced extracellular VEGFR-2 labeling in SHR mesenteric microvessels.
- MMP inhibition attenuated both VEGFR-2 cleavage and microvascular rarefaction in SHR.
Conclusions:
- MMP-induced cleavage of the extracellular domain of VEGFR-2 is spatially linked to microvascular rarefaction in the SHR mesentery.
- MMPs play a significant role in regulating microvascular dysfunction associated with hypertension.
- Targeting MMPs may offer a therapeutic strategy for hypertension-related vascular complications.
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