Abstract 300: Targeted Deletion of Matrix Metalloproteinase 2 Prevents Angiotensin II-Induced Endothelial Dysfunction and Vascular Remodeling, Oxidative Stress and Inflammation

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Abstract

Background: Matrix metalloproteinase 2 (MMP2) is involved in vascular remodeling in atherosclerosis. Whether MMP2 plays a role in angiotensin (Ang) II-induced hypertension, vascular remodeling, oxidative stress and inflammation is unknown. We hypothesized that Mmp2 knockout will prevent Ang II-induced vascular injury.

Methods: Ten to 12-week-old male Mmp2 knockout (Mmp2-/-) and wild type (WT) mice were infused with Ang II (1000 ng/kg/min, sc) for 14 days. Systolic blood pressure (SBP) was measured by telemetry. Mesenteric arteries (MA) were studied by pressurized myography. NADPH oxidase activity was evaluated by lucigenin chemiluminescence, and aortic reactive oxygen species (ROS) generation using dihydroethidium staining. Aortic expression of vascular cell adhesion protein 1 (VCAM-1) and monocyte chemotactic protein-1 (MCP-1), and monocyte/macrophage infiltration were assessed by immunofluorescence. Spleen T cells and monocytes were assessed by flow cytometry.

Results: Ang II increased SBP by 50 mmHg (P<0.01), decreased vasodilatory responses to acetylcholine by 70 % (P<0.01), induced MA hypertrophic remodeling, indicated by a 1.5-fold increase (P<0.01) in media-to-lumen ratio and 1.3-fold increase (P<0.05) in media cross-sectional area, and enhanced MA stiffness (P<0.01), as shown by a leftward shift of the stress/strain relationship, in WT mice. Ang II increased NADPH oxidase activity 1.4-fold in aorta (P<0.05), 2-fold in the heart (P<0.01) and 2.6-fold in the renal cortex (P<0.01) and aortic ROS generation 25-fold in WT mice (P<0.01). Ang II increased aortic VCAM-1 and MCP-1 expression 3- and 6-fold, respectively, and monocyte/macrophage infiltration 8-fold in WT (P<0.05). Ang II increased ≥1.8-fold spleen activated CD4+CD69+ and CD8+CD69+ T cells and pro-inflammatory Ly-6Chi monocytes (P<0.001) in WT mice. Mmp knockout prevented or reduced all of the above except SBP elevation (P<0.05).

Conclusion: MMP2 plays a role in Ang II-induced endothelial dysfunction, vascular remodeling, oxidative stress and inflammation but not in blood pressure elevation.

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