MMP-2 and MMP-9 activities are modulated by nitric oxide in fetal heart and placenta of diabetic rats at mid-gestation.

PUSTOVRH C.; JAWERBAUM A.; CAPOBIANCO E.; WHITE V.; MARTINEZ N.; HIGA R.; LÓPEZ-COSTA J.J.; PAZ D.A.; GONZÁLEZ E.

Cambridge, UK

Congreso; 33rd Meeting of the Fetal and Neonatal Physiological Society; 2006

Diabetic pathology produces placental and fetal alterations that involve the increases of matrix metalloproteinases (MMPs). MMPs are important enzymes associated with tissue remodeling, growth and differentiation. These enzymes could be modulated by different agents who disrupt its cysteine switch leading to its activation. In other tissues, nitric oxide (NO) ia able to promote MMPs activation. The aim of the present work was to evaluate the localization of MMPs and Nitric Oxide (NOS) and to study the influence of NO on MMP-2 and MMP-9 activities in tne feto-placental unit from control and diabetic rats. METHOD Rats were made diabetic by neonatal administration of streptozotocin (90 mg/kg) a method that leads to mild hyperglycemia (150-230 mg/dl) in the adult. Fetal and placental tissues (maternal and fetal placental sides) from diabetic rats (D) and controls © were evaluated on day 13.5 of pregnancy. MMPs and iNOS distribution were evaluated by double immunolabelling using confocal microscopy. NO synthase (NOS) activity was evaluated in situ by NADPH-diaphorase (NADPH-d) histochemistry. The effect of NO on MMP-2 and MMP-9 activities was measured after 1 h incubation with or without additions of either a NO donor (sodium nitroprusside (NP) 600uM) or a NOS inhibitor (L-NAME 600 mM). RESULTS NADPH-d activity was enhanced inD placenta when compared to C, mostly in the labyrinth zone. In C and D placenta, NP additions increased MMP-9 activity (30%, P<0.05) in the  maternal side while NAME additions reduced MMP-9 and MMP-2 activities in both maternal (22%,P<0.05) and fetal (20, P<0.05) sides. In C and D heart fetuses, NADPH-d activity was enhanced inD when compared to C. MMP-2 and iNOS label presented different expressions in D and C fetus and showed co-localization in the ventricular septum. In the fetuses, NP additions increased MMP-2 activity (30% and 48% respectively, P<0.01) while NAME reduced its activity (25% and 40% respectively, P<0.01). CONCLUTIONS Our results showed that MMPs activities are up-regulated by NO. In maternal diabetes, overactivation of MMPs in the feto-placental unit may be the result of increased NO levels and probably lead to abnormal remodeling processes.