Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats

Abstract

Tong W, Xue Q, Li Y, Zhang L. Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats. Am J Physiol Heart Circ Physiol 301: H2113-H2121, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00356.2011.-Fetal hypoxia leads to progressive cardiac remodeling in rat offspring. The present study tested the hypothesis that maternal hypoxia results in reprogramming of matrix metalloproteinase (MMP) expression patterns and fibrillar collagen matrix in the developing heart. Pregnant rats were treated with normoxia or hypoxia (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from 21-day fetuses (E21) and postnatal day 7 pups (PD7). Maternal hypoxia caused a decrease in the body weight of both E21 and PD7. The heart-to-body weight ratio was increased in E21 but not in PD7. Left ventricular myocardium wall thickness and cardiomyocyte proliferation were significantly decreased in both fetal and neonatal hearts. Hypoxia had no effect on fibrillar collagen content in the fetal heart, but significantly increased the collagen content in the neonatal heart. Western blotting revealed that maternal hypoxia significantly increased collagen I, but not collagen III, levels in the neonatal heart. Maternal hypoxia decreased MMP-1 but increased MMP-13 and membrane type (MT)1-MMP in the fetal heart. In the neonatal heart, MMP-1 and MMP-13 were significantly increased. Active MMP-2 and MMP-9 levels and activities were not altered in either fetal or neonatal hearts. Hypoxia significantly increased tissue inhibitors of metalloproteinase (TIMP)-3 and TIMP-4 in both fetal and neonatal hearts. In contrast, TIMP-1 and TIMP-2 were not affected. The results demonstrate that in utero hypoxia reprograms the expression patterns of MMPs and TIMPs and causes cardiac tissue remodeling with the increased collagen deposition in the developing heart.

Hypoxia inhibits cardiomyocyte proliferation in fetal rat hearts via upregulating TIMP-4

“…To determine whether potential mediators TIMP-3 and TIMP-4 were involved in the hypoxia-mediated downregulation of cardiomyocyte proliferation, the expression of TIMP-3 and TIMP-4 was measured by Western blot analysis. Consistent with the previous in vivo findings in fetal rat hearts of maternal hypoxia (38), ex vivo hypoxic treatment caused a significant increase in both TIMP-3 and TIMP-4 protein abundance, demonstrating a direct effect of hypoxia on the upregulation of TIMP-3 and TIMP-4 expression in fetal hearts (Fig. 3A).…”

“…The long-term detrimental effects of fetal growth restriction on the development of cardiovascular disease in later adult life have been well established (2,3,10,23). Recent studies in a rat model of maternal hypoxia and fetal growth restriction demonstrated a decrease in cardiomyocyte proliferation and premature transition of mononucleated cells to binucleated cells with increased cell sizes in the fetal heart (1,38). In rat heart development, the transition of proliferative and hyperplasic growth of mononucleated cells to hypertrophic growth of binucleated cells and terminal differentiation of cardiomyocytes take place within the first 2 wk after birth (5).…”

“…The hypoxia-mediated premature exit of the cell cycle with disproportional increases in terminally differentiated cardiomyocytes in the heart of growth-restricted fetuses suggests an early morphological indication of cardiomyocyte hypertrophy resulting in fewer but larger cardiomyocytes in the heart of offspring (20,44). A fetal hypoxia-mediated decrease in cardiomyocyte proliferation was associated with altered expression patterns of matrix metalloproteinases (MMPs) and increased collagen deposition in the heart (38). The functional impact of these changes has been demonstrated in adult offspring in which a sustained reduction of MMP-2 and enhanced collagen accumulation were found in the heart along with left ventricular hypertrophy and stiffening, diastolic dysfunction, and heightened vulnerability to ischemic injury (20, 21, 31, 38, 44 -46).…”

“…Additionally, little is known about the mechanisms linking fetal hypoxia and the inhibition of cardiomyocyte proliferation in the fetal heart. Our recent studies have demonstrated that maternal hypoxia significantly increased the expression levels of tissue inhibitor of metalloproteinase (TIMP)-3 (TIMP-3) and -4 (TIMP-4) in the fetal heart (38). In addition to their roles in modulating MMPs, it has been suggested that both TIMP-3 and TIMP-4 may be involved in inhibiting cardiomyocyte proliferation in rat hearts possibly via a MMP independent and receptor-mediated manner (12,13,40).…”

Preeclampsia, prematurity and cardiovascular health in adult life

“…As such, offspring of preeclamptic pregnancies develop in an environment of placental insufficiency, restricted oxygen supply [28] and abnormal levels of circulating antiangiogenic factors in the mother [29]. Animal studies indicate exposure to hypoxia related to abnormal placental development results in elevated myocardial collagen [30]. This is consistent with findings in newborn pigs, whereby short-term exposure to hypoxemia led to sustained reductions in longitudinal peak systolic strain [31].…”