Reductions of Circulating Nitric Oxide are Followed by Hypertension during Pregnancy and Increased Activity of Matrix Metalloproteinases-2 and -9 in Rats

Abstract

Hypertensive pregnancy has been associated with reduced nitric oxide (NO), bioavailability, and increased activity of matrix metalloproteinases (MMPs). However, it is unclear if MMPs activation is regulated by NO during pregnancy. To this end, we examined activity of MMP-2 and MMP-9 in plasma, placenta, uterus and aorta, NO bioavailability, oxidative stress, systolic blood pressure (SBP), and fetal-placental development at the early, middle, and late pregnancy stages in normotensive and Nω-Nitro-L-arginine methyl-ester (L-NAME)-induced hypertensive pregnancy in rats. Reduced MMP-2 activity in uterus, placenta, and aorta and reduced MMP-9 activity in plasma and placenta with concomitant increased NO levels were found in normotensive pregnant rats. By contrast, increased MMP-2 activity in uterus, placenta, and aorta, and increased MMP-9 activity in plasma and placenta with concomitant reduced NO levels were observed in hypertensive pregnant rats. Also, elevated oxidative stress was displayed by hypertensive pregnant rats at the middle and late stages. These findings in the L-NAME-treated pregnant rats were also followed by increases in SBP and associated with fetal growth restrictions at the middle and late pregnancy stages. We concluded that NO bioavailability may regulate MMPs activation during normal and hypertensive pregnancy.

Extracellular Matrix in Aging Aorta

“…Aberrant cell-ECM interactions also reduce NO bioavailability and impair endothelial-dependent vasodilation (Paar et al, 2014). Decreased NO bioavailability also stimulates activation of MMPs (Nascimento et al, 2019), which further degrades the matrix composition of the aortic wall, particularly within collagen and elastic fibers (Tronc et al, 2000;Upchurch et al, 2001;Zaragoza et al, 2002). These changes in the intima layer contribute to aortic aging and pathogenesis of CVDs (inside-out theory: inner layer triggers remodeling of aortic wall) (Donato et al, 2015;Yin and Pickering, 2016).…”

Age- and Phenotype-Dependent Changes in Circulating MMP-2 and MMP-9 Activities in Normotensive and Hypertensive Rats

“…The role of circulating MMP-2 and MMP-9 in the etiopathogenesis of essential hypertension has not yet been studied in connection with age [ 15 , 16 , 17 ]. We monitored MMP-2 and MMP-9 activities along with oxidative stress and antioxidant capacity parameters due to possible direct MMP activation under conditions of increased oxidative stress [ 18 ].…”

“…MMP-9 has a similar role to MMP-2; both are involved in the proteolytic activation of many cytokines [ 13 , 14 ]. The role of MMP-2 and MMP-9 in the etiopathogenesis of essential hypertension is documented in a number of studies, but none of them comprehensively address their age-dependent activation [ 15 , 16 , 17 ].…”

Magnesium Lithospermate B Downregulates the Levels of Blood Pressure, Inflammation, and Oxidative Stress in Pregnant Rats with Hypertension

“…Pregnant rats were normally bred until day 15 of pregnancy, and then a total of 40 pregnant female rats were equally assigned to four groups (10 rats each group) and additionally received indicated reagents besides normal diet: (і) control, rats were fed with normal saline; (ii) PIH, rats were orally given 60 mg/kg/day L-NAME for one week [ 17 ]; (iii) MLB 5 mg/kg, rats were orally given 60 mg/kg/day L-NAME and intraperitoneally administrated 5 mg/kg/day MLB for one week; and (iv) 10 mg/kg MLB, rats were orally given 60 mg/kg/day L-NAME and intraperitoneally administrated 10 mg/kg/day MLB for one week.…”