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出生的重婴儿的3-5倍。与出生体重一样，胎儿生长发育指数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，产前发育不足和患冠心病的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一种假设，即宫内应激源，如缺氧、高血压和容量负荷，将导致基因表达模式的适应性补偿，这将为胎儿立即生存适应做好准备，但会使后代面临成人发病的风险。在过去的资助期间，人们发现血管紧张素II不会在体内或体外刺激肥大，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，旨在揭示可能导致终生心血管疾病倾向的适应机制。1)测定胎儿对压力负荷和贫血的生理、组织学、细胞和生化反应，并确定心肌细胞与冠状动脉生长的关系。如果心脏与生俱来的细胞太少，它可能容易失败。2)确定胎儿应激源对成人心功能和冠脉传导的影响。如果电导过高，冠脉内皮细胞可能会出现切应力疲劳。3)确定丝裂原活化蛋白激酶(MAPK)信号级联中的一个特定成员(MAPK)在调节胎儿心脏增生与肥大生长中的作用。在体内和体外实验中，当心脏被刺激生长时，MEK都会被阻断。如果MEK被阻断，压力诱导的心肌细胞增殖可能被阻止。

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.