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Extra- and intracellular activation of matrix metalloproteinase-2 by oxidative stress in arterial hypertension-induced vascular remodeling via extracellular matrix dependent- and independent mechanisms


Hypertension significantly leads to vascular hypertrophic remodeling and dysfunction that usually precedes the development of many cardiovascular diseases. Increased matrix metalloproteinase (MMP)-2 activity contributes to cause vascular smooth muscle cells to hypertrophy and proliferate during the remodeling of hypertension. In fact, by inhibiting MMP activity, the incidence of the maladaptive remodeling decreases as it decreases the vascular smooth muscle cells proliferation and hypertrophy. However, mechanisms used by MMP-2 to cause arterial hypertrophic remodeling were not completely explored and this is the focus of this project. Intracellular MMP-2 activation by oxidative stress may be a potential mechanism that contributes to hypertension-induced arterial remodeling as it is observed that MMP-2 may cleave intracellular proteins in the vascular smooth muscle cells to contribute to proliferation. SERCA was chosen as a potential target of proteolysis by MMP-2 as its loss may contribute to increase calcium concentration and then accentuated vasoconstriction and remodeling in hypertension. It is needed to design MMP inhibitors that specifically inhibit either the extra- or intracellular forms of MMP to attempt to reduce maladaptive vascular remodeling of hypertension. Therefore, it is important to understand the mechanisms that contribute to the proteolytic actions of MMPs in the vasculature during hypertension. To establish this, the 2K-1C hypertension model and treatment with doxycycline will be used. Type I collagen and SERCA will be examined in this project as potential targets to be degraded by MMP-2 extra- and intracellularly in hypertension, since they regulate vascular smooth muscle cell proliferation and hypertrophy. The results from this project will assist and help to find solutions of how the vascular remodeling is regulated and then controlled in hypertension. (AU)

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(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE OLIVEIRA NEVES, VIVIANO GOMES; DE MELLO, MARCELA M. BLASCKE; RODRIGUES, DANIEL; PERNOMIAN, LAENA; DE OLIVEIRA, ISADORA SOUSA; PARENTE, JULIANA M.; ARANTES, ELIANE CANDIANI; TOSTES, RITA C.; CASTRO, MICHELE M.. Type I collagen proteolysis by matrix metalloproteinase-2 contributes to focal adhesion kinase activation and vascular smooth muscle cell proliferation in the aorta in early hypertension. VASCULAR PHARMACOLOGY, v. 152, p. 9-pg., . (19/10173-6, 20/13176-3, 19/09174-8)

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