Fetal stressors alter long-term myocyte /coronary growth

足月出生的小婴儿患缺血性心脏病的可能性是非糖尿病母亲所生的超重婴儿的3-5倍。胎儿生长指数，如出生体重，是一个独立的风险因素，比美国心脏协会认可的众所周知的风险因素更强大。然而，产前生长不足和冠状动脉疾病倾向之间的生物学联系是难以捉摸的。这一应用是基于这样的假设，即宫内应激源如缺氧、高血压和容量负荷会导致基因表达模式的适应性补偿，这将使胎儿“程序化”，以适应即时生存，但使后代面临成年发病疾病的风险。在过去的资助期内，人们发现血管紧张素II在体内或体外都不会刺激肥厚，这与目前基于大鼠数据的教条完全相反。该提案包含3个目标，旨在揭示可能导致心血管疾病终身倾向的适应性机制。1)确定胎儿对压力负荷和贫血的生理、组织学、细胞和生化反应，确定心肌细胞与冠状动脉生长的关系。如果心脏出生时细胞太少，它可能容易衰竭。2)确定胎儿应激源对成人心功能和冠状动脉传导的影响。如果传导过高，冠状动脉内皮可能发生剪切应力疲劳。3)确定有丝分裂原活化蛋白激酶（MAPK）信号级联（MAP激酶称为MEK）的特定成员在调节胎儿心脏增生与肥厚生长中的作用。在体内和体外实验中，当心脏受到刺激生长时，MEK都会被阻断。如果MEK被阻断，可能会阻止压力诱导的心肌细胞增殖。

Babies born small at full term are 3-5 times more likely to contract ischemic heart disease than are heavy babies born to non-diabetic mothers. An index of fetal growth, like birth weight, is an independent risk factor more powerful than the well-known risk factors endorsed by the American Heart Association. However, the biological link between prenatal undergrowth and the propensity to contract coronary disease is elusive. This application is based on the hypothesis that intrauterine stressors such as hypoxia, hypertension and volume load will cause adaptive compensations of the gene expression pattern that will "program" the fetus for immediate survival adaptation but put the offspring at risk for adult-onset disease. During the past funding period, it was discovered that angiotensin II does not stimulate hypertrophy in vivo or in vitro, quite contrary to current dogma based on rat data. The proposal contains 3 aims designed to uncover adaptive mechanisms that are likely to bring about a life long propensity to cardiovascular disease. 1) Determine the physiological, histological, cellular and biochemical response to pressure loading and anemia in the fetus and determine the relationship between the myocyte and coronary growth. If the heart is born with too few cells, it may be failure-prone. 2) Determine the effects of fetal stressors on adult heart function and coronary conductance. If conductance is too high, the coronary endothelium may suffer from shear stress fatigue. 3) Determine the role of a specific member of the mitogen activated protein kinase (MAPK) signaling cascade (MAP kinase kinase called MEK) in regulating fetal cardiac hyperplasia versus hypertrophic growth. MEK will be blocked in both in vivo and in vitro experiments while the heart is being stimulated to grow. If MEK is blocked, pressure- induced cardiomyocyte proliferation may be prevented.