Prenatal treatment with glucocorticoids contributes to the reduction of Tregs, increased MMP-2 activity, and vascular remodeling and dysfunction in the adult life of the offspring

• Grant number: 24/02701-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: July 01, 2024
• End date: June 30, 2026
• Field of knowledge: Health Sciences - Medicine - Maternal and Child Health
• Principal Investigator: Michele Mazzaron de Castro
• Grantee: Marcela Maria Blascke de Mello
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Preterm birth is associated with increased risk of cardiovascular diseases in adulthood, such as hypertension, and is characterized by respiratory distress syndrome, which increases morbidity and mortality in newborns. Prenatal treatment with corticosteroids is an alternative in cases of risk of preterm birth, as it accelerates fetal lung maturation. On the other hand, prolonged use of prenatal corticosteroids can lead to intrauterine growth restriction and an increased risk of developing arterial hypertension. Furthermore, the administration of corticosteroids also impairs the development of the immune system, such as the expression and maturation of T lymphocytes, as it has immunosuppressive action; however, it is necessary to investigate this effect specifically on regulatory T cells (Tregs). The expression of Tregs is regulated by the complement system and oxidative stress, thus suggesting a correlation between the components of this pathway. Furthermore, both oxidative stress and the complement system can activate MMP-2, an important protease for arterial remodeling in hypertension. Knowing this, the hypothesis is that prenatal treatment with glucocorticoid presents immunomodulatory effects and increases the activity and expression of MMP-2 in adult offspring, which results in vascular remodeling and dysfunction as risk factors for the development of hypertension. For this, pregnant Sprague-Dawley rats will be treated with dexamethasone or vehicle during pregnancy and the offspring will be studied in adulthood, after Tregs transfusion, to evaluate the following parameters: expression of Foxp3, C3a, C3aR, MMP- 2, IL-6 and IL-10 by Western Blot and/or RT-PCR; MMP-2 activity by gel and in situ zymography; oxidative stress by in situ DHE and IHC for nitrotyrosine; analysis of arterial remodeling and inflammatory infiltrate by H&E staining; labeling of CD4, CD25 and CD127 in flow cytometry; vascular reactivity in response to phenylephrine and acetylcholine.