NHLBI CLINICAL INVESTIGATOR AWARD PROGRAM

我一直在做一个豚鼠模型， 高血压 我们发现， 高血压和血管重构与平滑肌 在该模型中发生肌肉增生。 此外，本发明还提供了一种方法， 存在血小板减少症，可能是由于血小板 粘附于肺血管。 肺 高血压、血管重塑和血小板减少症都是 部分通过肝素治疗得以预防。 这些 结合文献中的其他数据的观察表明， 平滑肌细胞增生和血小板粘附可能是由于 缺氧引起的内皮细胞变化。 肝素可能会干扰这些变化， 未知的机制 一方面，内皮源性丝裂原 对于平滑肌增殖已经有了描述， 另一方面，已经观察到， 抑制平滑肌增殖。 乙酰肝素 硫酸盐在暴露于缺氧的内皮细胞中被抑制， 这表明这种糖胺聚糖可以调节平滑肌细胞， 缺氧引起的肌肉增生。 我计划在拟议的 研究：1）探索细胞的共培养以评估效果 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）评估可能的 由内皮细胞产生的有丝分裂原; 3）评估 硫酸乙酰肝素作为一种可能的调节剂， 平滑肌和成纤维细胞增殖; 4）评估影响 缺氧对内皮细胞粘附凝血酶特性的影响 和血小板，并评估肝素对粘附的影响;以及 5)评价缺氧对血管内皮细胞和平滑肌细胞的影响 肌肉钙离子和环核苷酸代谢 缺氧产生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.