NHLBI CLINICAL INVESTIGATOR AWARD PROGRAM

我一直在研究缺氧性肺损伤的豚鼠模型。 高血压。我们发现显著的慢性肺病 高血压和血管重构与血管顺畅相关 在这种模式下，肌肉会发生增生。此外, 存在血小板减少症，可能是由于血小板引起的。 附着在肺血管系统上。肺 高血压、血管重塑和血小板减少都是 可通过肝素治疗部分预防。这些 结合文献中的其他数据，观察表明 可能是由于平滑肌细胞增生和血小板粘连 对缺氧引起的血管内皮细胞改变的影响。 肝素可能会干扰这些改变，目前 未知的机制。一方面，内皮源性丝裂原 对平滑肌增殖的作用已经被描述过了，而且在 另一方面，已经观察到类似肝素的物质来源于 抑制血管内皮细胞的增殖。肝素 暴露在低氧环境中的内皮细胞中硫酸盐被抑制， 提示这种糖胺多聚糖可能调节平滑 由低氧引起的肌肉增殖。我计划在提议的 研究1)探索细胞共培养以评估其效果 缺氧对内皮细胞/平滑肌细胞相互作用的影响 对平滑肌和成纤维细胞增殖的影响 肝素在体外影响这些过程；2)评估可能性 内皮细胞产生的有丝分裂原；3)评估合成 硫酸乙酰肝素在血管内皮细胞中可能的调节作用 平滑肌和成纤维细胞的增殖；4)评估其影响 缺氧对内皮细胞黏附凝血酶特性的影响 和血小板，并评估肝素对黏附的影响； 5)评价缺氧对血管内皮细胞和血管内皮细胞的影响 可能的肌肉钙离子和环核苷酸代谢 缺氧引起的增殖性变化的信使。

I have been working on a guinea pig model of hypoxic pulmonary hypertension. We have found that significant chronic pulmonary hypertension and vascular remodeling associated with smooth muscle hyperplasia occurs in this model. In addition, thrombocytopenia is present and is probably due to platelet adherence to the pulmonary vasculature. The pulmonary hypertension, vascular remodeling, and thrombocytopenia are all partially prevented by treatment with heparin. These observations coupled with other data in the literature suggest that smooth muscle cell hyperplasia and platelet adhesion may be due to cellular changes of the endothelium induced by hypoxia. Heparin may interfere with these alterations by currently unknown mechanisms. On one hand, endothelial derived mitogen for smooth muscle proliferation has been described, and on the other hand it has been observed that heparin-like material derived from endothelium inhibits smooth muscle proliferation. Heparan sulfate is depressed in endothelial cells exposed to hypoxia, suggesting that this glycosaminoglycan may regulate smooth muscle proliferation produced by hypoxia. I plan in the proposed studies to 1) explore co-cultures of cells to evaluate the effects of hypoxia on endothelial cell/smooth muscle cell interaction and on smooth muscle and fibroblast proliferation and determine if heparin influences these processes in vitro; 2) assess possible mitogens produced by endothelial cells; 3) evaluate synthesis of heparan sulfate by the endothelial cell as a possible regulator of smooth muscle and fibroblast proliferation; 4) assess the influence of hypoxia on endothelial cell adherence properties for thrombin and platelets and evaluate the effect of heparin on adherence; and 5) evaluate the influence of hypoxia on endothelial and smooth muscle Ca2+ and cyclic nucleotide metabolism as possible messengers for proliferative changes produced by hypoxia.