Abstract
Objective:
Matrix metalloproteinase-2 (MMP2) participates in the mechanisms of vascular injury in atherosclerosis. Whether MMP2 plays a role in angiotensin (Ang) II-induced hypertension and vascular remodeling is unknown. We hypothesized that
Mmp2
knockout (
Mmp2
-/-
) would prevent Ang II-induced hypertension and vascular injury.
Methods and Results:
Fourteen days of Ang II infusion (1000 ng/kg/min, SC) increased systolic blood pressure (SBP, 161±9 vs 122±3 mm Hg,
P
<0.05) and decreased vasodilatory responses to acetylcholine (33±5 vs 83±3%,
P
<0.001), increased the media/lumen (4.8±0.4 vs 3.1±0.1%,
P
<0.001) and media cross-sectional area (7223±467 vs 5346±336 μm
2
,
P
<0.05) and enhanced stiffness (
P
<0.05), as shown by a leftward shift of the stress/strain relationship of mesenteric arteries in wild-type mice. Ang II enhanced aortic (73±6 vs 6±1 relative fluorescence units [RFU]/μm
2
,
P
<0.001) and perivascular adipose tissue (PVAT) reactive oxygen species generation (76±11 vs 12±1 RFU/μm
2
,
P
<0.001), aortic VCAM-1 (17±3 vs 5±1 RFU/μm
2
,
P
<0.001) and MCP-1 expression (71±14 vs 11±3 RFU/μm
2
,
P
<0.001), PVAT monocyte/macrophage (1.8±0.3 vs 0.1±0.1 % of PVAT,
P
<0.001) and T cell infiltration (56±14 vs 16±9 cells/μm
2
,
P
<0.05) and the fraction of spleen activated CD4
+
CD69
+
(17±2 vs 10±1 % of CD4+ T cells,
P
<0.001), CD8
+
CD69
+
T cells (11±1 vs 5±1 % of CD4+ T cells,
P
<0.001) and Ly-6C
hi
monocytes (53±6 vs 25±2 % event,
P
<0.001). Ang II increased phosphorylation of epidermal growth factor receptor 1.9±0.2-fold and extracellular-signal-regulated kinase 1/2 1.4±0.1-fold in vascular smooth muscle cells isolated from mesenteric arteries of wild-type mice (
P
<0.05).
Mmp2
knockout prevented or reduced all of the above (
P
<0.05) except SBP elevation. Bone marrow transplantation experiments revealed that Ang II-induced hypertension was impaired in absence of immune cell MMP2 and endothelial dysfunction was blunted or reduced in absence of immune or vascular cell MMP2 (
P
<0.05).
Conclusions:
Mmp2
knockout prevented Ang II-induced vascular injury but not hypertension. Bone marrow transplantation experiments revealed a complex relationship of immune and vascular cell MMP2 in the development of Ang II-induced hypertension and endothelial dysfunction.