The Role Of Intrauterine Chronic Hypoxia On The Development Of Atherosclerosis In Rats Offspring And Its Mechanism

Atherosclerosis has already become a world-wide public health issue due to its aggressive hazard to human beings. Recent studies indicate a correlation between adverse intrauterine environment and an increased risk of atherosclerosis in later adult life. Chronic hypoxia during the course of pregnancy is one of the most common and clinically relevant insults to the fetus. It will bring us extensive theoretical and practical significance that studies on the role of chronic hypoxia exposure during gestation on atherosclerosis in the adult. In this study, three Sprague-Dawley rats animal models of intrauterine chromic hypoxia (ICH), hyperlipemia, adult hypoxia and one vitro cell culture model of vascular smooth muscle cells (VSMC) have been utilized to investigate the effects of intrauterine chronic hypoxia on the development of atherosclerosis in the offspring rats and its mechanism.In the present study, we demonstrated that ICH was one of the insults to prompt fetal programming that led to characteristic histological changes of the early stage atherosclerosis in fetal hypoxia offspring, which can be synergistic with hyperlipemia. ICH resulted in remarkably up-regulated apoptosis in offspring blood vessel. The apoptosis rate was significantly elevated in 16 months old ICH offspring as compared with controls (38.8±8.5% vs 15.8±5.8%,t=6.90,P<0.001), with obviously up-regulation of caspase-3 expression and down-regulation of bcl-2 in the thoracic aorta. Furthermore, ICH led to an impaired vascular endothelial function in the offspring. The endothelial dependent diastolic function was prominently decreased in ICH offspring (45.1±14.4% vs 82.7±10.6%,t=5.14,P<0.001), with a significant decrease in eNOS level and increase in iNOS in the aorta. Moreover, ICH can induce fetal programming in IGF-1 axis. Compared with controls, serum IGF-1 level was decreased at pregnancy day 21 and increased in 20 days old (all P<0.01), whereas IGF-1 receptor expression was persistently diminished in the aorta of ICH group. Our vitro study demonstrated that ICH predominantly attenuated the IGF-1-induced cell proliferation and antiapoptotic efficacy of VSMC from offspring rats. IGF-1-induced cell proliferation rate was significantly reduced in ICH cell as compared with the controls (all P<0.05). In contrast, the serum starvation-induced apoptotic nuclei rate and caspase-3 activity in ICH cell were prominently higher than that in controls after incubation with IGF-1 in serum free medium (all P<0.05). It was also reduced the ability of IGF-1 to induce Akt phosphorylation in ICH cells, which presented an impaired IGF-1 post-receptor signaling pathways.Taken together, these results revealed that ICH can cause fetal programming in apoptosis, vascular endothelial function and IGF-1 axis that induce adult-onset atherosclerosis in the offspring rats. Among of them, IGF-1 axia programming might play the most important role in the ICH induced atherosclerosis. ICH inhibited the physiologic function of IGF-1 axis by inducing IGF-1 signaling resistance, which led to up-regulated apoptosis and impaired vascular endothelial function, and precipitated the development of atherosclerosis in offspring rats.