DETERMINANTS OF CORONARY COLLATERAL DEVELOPMENT

在过去的七年里，我们已经开发了一种慢性缺血的猪模型， 这为研究侧枝发育的机制提供了机会， 持续运动引起的慢性脑缺血和适应 缺血心肌根据这些观察，我们现在假设（1） 药物干预对冠状动脉侧支循环的影响 发展取决于干预的发展阶段 发生;（2）血管生成生长因子对冠状动脉侧支循环的影响 可以通过阻断炎症反应来改变发育 与心肌缺血性损伤相关;和（3）冠状动脉 缺氧的微血管内皮细胞的生长 特征、促分裂原反应和白细胞粘附反应， 也会改变抵押品的增长。在这次修订后的更新中，我们的具体目标是 已经被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)以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 在早期（0-5周）和晚期（5-10周）阶段进行研究， 发展干预措施将包括肝素和多巴酚丁胺（单独 SKF TL 94424 -4、烟酰胺和三碘甲状腺原氨酸 (T-3)（2）在以下条件下表征床中脉管系统的形态测量学特征： 风险作为血管生成和重塑发生;（3）阻止的影响， 血管生成生长因子来源于巨噬细胞和血小板， 冠状动脉闭塞的炎症反应;（4）表征 冠状动脉内皮细胞的生长和丝裂原反应 猪的微血管和动脉以及心房冠状动脉 微血管和脐静脉（HUVEC），并研究 人心房冠状动脉白细胞粘附分子的细胞生物学研究 微血管内皮细胞，与已知的HUVEC标准相比; (5)研究猪等同物的发生和细胞生物学， 人白细胞粘附分子，即ELAM、ICAM-1、ICAM-2和GMP-140， 在猪内皮细胞（PEC）培养物中， 猪的微血管这些研究将集中在体外反应 PEC的缺氧，新的蛋白质或RNA合成的需要， 白细胞源性细胞因子对细胞因子相对表达的影响 粘附分子这些研究将检查4种粘附的作用， 分子在炎症反应的产生，促进 心肌缺血早期侧支生长;（6） 测定血管生成生长因子（bFGF，aFGF， 在细胞水平通过原位cDNA：mRNA杂交检测PDGF和TGF的表达。 猪冠状动脉侧支形成模型。

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.