DETERMINANTS OF CORONARY COLLATERAL DEVELOPMENT

在过去的七年里，我们已经建立了一个慢性缺血的猪模型。 这为研究附带发展的机制提供了机会， 持续性运动性脑缺血与慢性脑缺血的适应 缺血心肌。根据这些观察，我们现在假设(1) 药物干预对冠脉侧支循环的影响 发展取决于干预所处的发展阶段 血管生成生长因子对冠脉侧支循环的影响 发育可以通过阻断炎症反应来改变 与心肌缺血性损伤有关；以及(3)冠状动脉 微血管内皮细胞在低氧条件下生长发生改变 特性、有丝分裂原反应和白细胞黏附反应 还可以调整抵押品增长。在这次修订的更新中，我们的具体目标是 已经进行了修改，以解决这些假设。 我们在这项拟议研究中的具体目标是： (1)确定药物干预是否会增加 抵押品开发和抵押品储备。这些干预措施将是 在早期(0-5周)和晚期(5-10周)进行研究 发展。干预措施将包括肝素和多巴酚丁胺(单独) 和组合)、SKF TL94424-4、烟酰胺和三碘甲腺原氨酸 (t-3)；(2)表征床上血管系统的形态计量学 血管生成和重塑的风险；(3)阻断血管生成和重构的影响 巨噬细胞和血小板来源的血管生成生长因子 冠状动脉闭塞时的炎症反应；(4)表征 冠状动脉内皮细胞的生长和丝裂原反应 猪和冠状动脉的微血管和主动脉 人的微血管和脐静脉(HUVEC) 人心房冠脉白细胞黏附分子的细胞生物学研究 微血管内皮细胞，与HUVEC的已知标准相比； (5)研究猪的等价物的发生和细胞生物学 人白细胞黏附分子，即ELAM、ICAM-1、ICAM-2和GMP-140， 猪血管内皮细胞(PEC)的培养 猪的微血管。这些研究将集中在体外反应上。 PEC对低氧的反应，对新蛋白质或RNA合成的需求，以及 白细胞衍生细胞因子对血管内皮细胞相对表达的影响 黏附分子。这些研究将检验4种黏附的作用。 促进炎症反应产生的分子 心肌缺血早期侧支生长；(6) 检测血管生成生长因子(bFGFa、aFGF3、 在细胞水平通过原位cDNAm RNA杂交检测 猪冠状动脉侧支循环发育模型的研究。

Over the last seven years we have developed a pig model of chronic ischemia which offers an opportunity to study mechanisms of collateral development, sustained exercise induced ischemia and adaptation of the chronically ischemic myocardium. From these observations we now hypothesize that (1) the effect of pharmacologic interventions on coronary collateral development depends on the stage of development in which the intervention occurs; (2) the effect of angiogenic growth factors on coronary collateral development can be modified by blocking the inflammatory response associated with ischemic injury to the myocardium; and (3) coronary microvascular endothelial cells subjected to hypoxia have altered growth characteristics, mitogen responses and leukocyte adhesion responses which also modify collateral growth. In this revised renewal our specific aims have been modified to address these hypotheses. Our specific aims in this proposed research are: (1) to determine if pharmacologic interventions will increase the rate of collateral development and collateral reserve. These interventions will be studied in the early (0-5 weeks) and late (5-10 weeks) stages of development. The interventions will include heparin and dobutamine (alone and in combination), SKF TL94424-4, nicotinamide and triiodothyronine (T-3); (2) to characterize the morphometry of the vasculature in the bed at risk as angiogenesis and remodeling occurs; (3) to block the effects of angiogenic growth factors derived from macrophages and platelets during the inflammatory response to coronary artery occlusion; (4) to characterize the growth and mitogen responses of endothelial cells derived from coronary microvasculature and aortas of pigs and from atrial coronary microvasculature and umbilical veins of humans (HUVEC) and to investigate the cell biology of leukocyte adherence molecules on human atrial coronary microvascular endothelial cells, compared to the known standard of HUVEC; (5) to study the occurrence and cell biology of porcine equivalents to the human leukocyte adhesion molecules, i.e. ELAM, ICAM-1, ICAM-2 and GMP-140, in porcine endothelial cell (PEC) cultures derived from aortae and coronary microvessels of the pig. These studies will focus on the in vitro response of PEC to hypoxia, the requirement for new protein or RNA synthesis and the influence of leukocyte-derived cytokines on the relative expression of the adhesion molecules. These studies will examine the roles of the 4 adhesion molecules in the generation of the inflammatory response which promotes collateral growth in the early stages of myocardial ischemia; (6) to determine the gene expression of angiogenic growth factors (bFGF, aFGF, PDGF and TGF) at the cellular level by in situ cDNA:mRNA hybridization in models of coronary collateral development in the pig.