Gestational and neonatal treatment with antioxidant or interleukin-10 decreases maladaptive arterial remodeling and Hypertension in the adult offspring of hypertensive rats through downregulating inflammatory mediators and MMP-2 activity

• Grant number: 22/04888-5
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2023
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Michele Mazzaron de Castro
• Grantee: Michele Mazzaron de Castro
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The inhibition of the maladaptive arterial remodeling contributes to prevent arterial hypertension. Earlier pharmacological intervention is important to control the incidence of such cardiovascular disease. Knowing that the quality of the intrauterine environment helps to develop hypertension, and the fetus is highly vulnerable to several insults, this period may be the most responsive to therapeutics with lasting benefits. Increased matrix metalloproteinase (MMP)-2 activity stimulates vascular smooth muscle cells to hypertrophy and proliferate during the remodeling of hypertension and then, its inhibition is an interesting pharmacological target to treat hypertension. However, the use of MMP inhibitors in the gestational period is not recommended as they may cause adverse effects to mother and fetus. It is important to know mechanisms that regulate MMP-2 expression and activity in the vasculature in order to decrease its effects in the development of hypertension in adult offspring of hypertensive rats. Oxidative stress increases inflammatory signalling and MMP-2 activity in hypertension-induced vascular dysfunction and remodeling. The use of antioxidants in the gestational period in hypertension may decrease MMP-2 activity, maladaptive remodeling and the incidence of hypertension in the adult offspring. Inflammatory mediators and oxidative stress will be examined as mechanisms that modulate the posttranslational activity of MMP-2 and the hypertrophic arterial remodeling in hypertension. Resveratrol or interleukin-10 will be used to treat female SHR rats during the gestational and lactation period to analyze whether oxidative stress and the complement system contribute to activate MMP-2, cause arterial remodeling and hypertension in their adult offspring. The identification of pharmacological target and its earlier management may contribute to ameliorate and/or reduce the incidence of hypertension in the population. (AU)

Scientific publications

(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 MELLO, MARCELA M. BLASCKE; NEVES, VIVIANO GOMES DE OLIVEIRA; PARENTE, JULIANA MONTENEGRO; PERNOMIAN, LAENA; DE OLIVEIRA, ISADORA SOUSA; PEDERSOLI, CARINA AMARANTE; AWATA, WANESSA MAYUMI CARVALHO; TIRAPELLI, CARLOS RENATO; ARANTES, ELIANE CANDIANI; TOSTES, RITA DE CASSIA A.; et al. Sarcoplasmic reticulum calcium ATPase (SERCA) proteolysis by matrix metalloproteinase-2 contributes to vascular dysfunction in early hypertension. European Journal of Pharmacology, v. 983, p. 9-pg., 2024-09-07. (19/09174-8, 21/11936-3, 20/13176-3, 20/02619-1, 22/04888-5)

PERNOMIAN, LAENA; DE MELLO, MARCELA M. BLASCKE; PARENTE, JULIANA MONTENEGRO; SANCHES-LOPES, JESSICA M.; TANUS-SANTOS, JOSE EDUARDO; PARREIRAS E SILVA, LUCIANA TABAJARA; ANTUNES-RODRIGUES, JOSE; DOS SANTOS, RAONI DA CONCEICAO; ELIAS, LUCILA LEICO KAGOHARA; FABRO, ALEXANDRE TODOROVIC; et al. The hydrogen sulfide donor 4-carboxyphenyl-isothiocyanate decreases blood pressure and promotes cardioprotective effect through reduction of oxidative stress and nuclear factor kappa B/matrix metalloproteinase (MMP)-2 axis in hypertension. Life Sciences, v. 351, p. 14-pg., 2024-06-14. (19/09174-8, 22/04888-5)