OS 15-02 MATRIX METALLOPROTEINASE 2 KNOCKOUT PROTECTS FROM ANGIOTENSIN II-INDUCED VASCULAR INJURY IN PART VIA INHIBITION OF EGFR AND ERK1/2 ACTIVATION

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Abstract

Objective:

Matrix metalloproteinase 2 (MMP2) is involved in cardiovascular disease. Whether MMP2 plays a role in hypertension and vascular damage is unknown. We hypothesized that Mmp2 knockout will prevent angiotensin (Ang) II-induced hypertension and vascular injury.

Design and Method:

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, and mesenteric artery (MA) endothelial function and vascular remodeling by pressurized myography. Reactive oxygen species (ROS) generation using dihydroethidium staining, and vascular cell adhesion protein 1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1) expression and monocyte/macrophage infiltration by immunofluorescence were determined in the aortic wall or perivascular fat (PVAT). Spleen T cell and monocyte profiles were assessed by flow cytometry. Vascular smooth muscle cells (VSMCs) were isolated from MA of WT and Mmp2−/− mice, stimulated 5 min with Ang II (100 nM) and epidermal growth factor receptor (EGFR) and extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation measured by Western blot.

Results:

Ang II increased SBP by 50 mmHg (P < 0.01), decreased by 50% MA vasodilator responses to acetylcholine (P < 0.01) and increased 1.7-fold MA media-to-lumen ratio (P < 0.01), 1.4-fold media cross-sectional area (P < 0.05), and stiffness (P < 0.01), as shown by a leftward shift of the stress/strain relationship, in WT. Furthermore, Ang II enhanced 12-fold aortic ROS generation (P < 0.01), 3.4-fold aortic VCAM-1 (P < 0.01), 6.5-fold MCP-1 expression (P < 0.01), 8-fold PVAT monocyte/macrophage infiltration (P < 0.05), and ∼2-fold spleen activated CD4+CD69+ and CD8+CD69+ T cells, and pro-inflammatory Ly-6Chi monocytes (P < 0.05) in WT. Ang II increased phosphorylation of EGFR 1.9-fold and ERK1/2 1.4-fold in VSMCs (P < 0.05). Mmp2 knockout prevented or reduced all of the above (P < 0.05) except SBP elevation.

Conclusions:

MMP2 plays an important role in Ang II-induced vascular injury, which could be mediated at least in part through EFGR and ERK1/2 activation in VSMCs.

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