THE ROLE OF MATRIX METALLOPROTEINASE (MMP)-2 TO TYPE I COLLAGEN TURNOVER CONTRIBUTING TO HYPERTROPHIC ARTERIAL REMODELING IN RENOVASCULAR HYPERTENSION

Abstract

Objective: Type I collagen proteolytic products contribute to VSMC proliferation via integrin receptor and focal adhesion kinase (FAK) activation. We then evaluated whether the early activation of MMP-2 in hypertension induces VSMC proliferation, due to type I collagen proteolysis, which may activate integrin and FAK to develop hypertrophic arterial remodeling. Design and method: Sprague Dawley rats were submitted to 2K1C surgery to induce hypertension and they were orally treated with doxycycline or vehicle (five days at first week (acute) and eight weeks at ten weeks of hypertension (chronic)); (CEUA-USP 165/2019). In the aorta, we evaluated the expression of MMP-2 and type I collagen by Western blotting; MMP-2 activity by gelatin and in situ zymography, arterial morphology by HE, and collagen deposition by picrosirius red. All statistical analyzes used two-way ANOVA followed by Tukey post hoc test with p < 0.05. Results: Our results showed that 2K1C rats developed high systolic blood pressure at the first week (156 ± 13 mmHg vs. Sham (p < 0,001)), which was progressively higher at ten weeks (219 ± 6 mmHg, p < 0,0001). Moreover, there was a significant increase in the MMP-2 expression and activity in the 2K1C rats at the first and tenth weeks of hypertension (p < 0.05). Treatment with doxycycline reduced MMP-2 activity only in the acute situation (p < 0.05). The 2K1C showed increased levels of type I collagen as well as its potential degradation products (p < 0.05) in the aorta during the first week of hypertension. However, the deposition of collagen was notably resynthesized in the aortas of chronic 2K1C rats (p < 0.05). Conclusions: Treatment with doxycycline reduced such effects in hypertensive rats. At this moment, we concluded that increased activity of MMP-2 may contribute to type I collagen proteolysis in aortas at early stages of hypertension, with its potential re-synthesis at late stages. This proteolytic effect of MMP-2 on collagen may contribute to stimulating VSMCs proliferation through integrins and FAK, mechanisms that we are currently investigating.