Matrix Metalloproteinase (MMP)‐2 Diverges in Regulate Calponin‐1 in Conductance and Resistance Arteries in Early Hypertension‐Induced Vascular Dysfunction and Remodeling

Abstract

IntroductionIncreased activity of MMP‐2 degrades many extra‐ and intracellular proteins, an effect that may contribute to hypertension‐induced vascular remodeling and dysfunction. Calponin‐1 is a differetiation marker of vascular smooth muscle cells (VSMC) and also inhibits Mg‐ATPase activity of myosin to regulate contraction. Calponin‐1 is an intracellular proteolytic target of MMP‐2 in aortas of hypertensive rats. The aim of this study is to investigate whether MMP‐2 contributes to hypertension‐induced vascular remodeling and dysfunction of conductance and resistance arteries by regulating calponin‐1.MethodsMale wistar rats were submitted to the two kidney‐one clip (2K‐1C) model of hypertension or sham surgery and were treated with doxycycline (inhibitor of MMPs, 30 mg/kg/day) or water for one week. Systolic blood pressure (SBP) was daily accessed by tail cuff plethysmography. After one week, aortas and mesenteric arteries were removed to analyze the activity of MMP‐2 by in situ zymography and calponin‐1 by immunofluorescence. Morphological analysis was performed with hematoxylin and eosin staining in aortas and pressurized myograph in mesenteric arteries. Immunohistochemistry to Ki‐67 was performed to analyze celular proliferation. Phenylephrine (PE) concentration‐effect curve was performed in aortas and in the third branch of mesenteric arteries by using tension myography. Statistical analysis were done by two‐way ANOVA. The Ethics Committee in Animal Research approved all protocols (012/2015‐1).ResultsSBP increased in the 2K‐1C rats (145.8±1.6 vs. 118.2±2.9, p<0,05) and treatment with doxycycline did not reduce it. The morphological analysis showed that 2K‐1C aortas had an increase in the media per lumen ratio (p<0,05) and cross‐sectional area (p<0,05) vs. Sham groups, an alteration that was not observed in mesenteric arteries at early hypertension. Furthermore, doxycycline was able to revert the increased VSMCs proliferation in aortas of 2K‐1C rats (p<0,05). On the other hand, PE significantly contracted more the mesenteric arteries of 2K‐1C (p<0.05 vs. Sham), and doxycycline reverted it. The potency of PE to contract aortas of 2K‐1C rats was higher than controls and doxycycline also reverted it. MMP‐2 activity was increased in both arterial bed of 2K‐1C rats and doxycycline reduced it (p<0,05). While calponin‐1 was lower in the aortas of 2K‐1C rats and treatment ameliorated it (p<0,05), its levels were increased in the 2K‐1C mesenteric arteries (p<0,05).ConclusionIn conductance arteries, the reduction of calponin‐1 by MMP‐2 contributed to VSMC proliferation and phenotype switch, which may result in the hypertrophic remodeling of hypertension. In resistance arteries, MMP‐2 may contribute to increase calponin‐1 as a regulatory mechanism to compensate hypertension‐induced increased vascular resistance. This effect may be particularly related to the extracellular mechanisms of MMP‐2.Support or Funding InformationCNPq, CAPES and FAPESP