Role of parathyroid hormone-related peptide in vascular stenosis.

血管平滑肌细胞（VSMCs）的增殖被认为是血管成形术后再狭窄病理生理学的一个关键事件。甲状旁腺激素相关肽（PTHrP）及其受体是多种正常细胞类型中细胞生长的局部自分泌和旁分泌调节剂，已报道在VSMCs附近存在。为了研究PTHrP如何参与球囊血管成形术后新内膜形成的过程，我们检测了球囊剥除的大鼠颈动脉和经定向动脉粥样硬化切除术恢复的人冠状动脉中PTHrP的表达。在大鼠颈动脉中，RNase保护实验和原位杂交表明，PTHrP mRNA表达在剥脱后1 ~ 7天增加4 ~ 6倍，并持续28天，与PTH/PTHrP受体mRNA表达下调一致。原位杂交和免疫组化显示PTHrP在球囊剥脱的颈动脉中主要表达于新生内膜。为了证实PTHrP参与人冠状动脉再狭窄病变，我们对人冠状动脉粥样硬化切除术标本（23例原发病变和10例再狭窄病变）进行免疫组织化学分析。再狭窄患者中表达PTHrP蛋白的内膜细胞数量明显高于稳定型和不稳定型心绞痛患者。这些数据表明，在血管内膜形成过程中，PTHrP基因在VSMC中的表达显著增加，支持了PTHrP可能作为VSMC增殖的调节剂在血管狭窄中发挥重要作用的假设。

Proliferation of vascular smooth muscle cells (VSMCs) is considered to be one key event underlying the pathophysiology of restenosis after angioplasty. The parathyroid hormone-related peptide (PTHrP) and its receptor, a local autocrine and paracrine regulator of cellular growth in a variety of normal cell types, have been reported in the vicinity of VSMCs. To investigate how PTHrP might be involved in the process of neointimal formation after balloon angioplasty, we examined PTHrP expression in balloon-denuded rat carotid arteries and human coronary arteries that had been retrieved by directional atherectomy. In rat carotid arteries, the RNase protection assay and in situ hybridization demonstrated that PTHrP mRNA expression increased fourfold to sixfold 1 to 7 days after denudation and continued for 28 days, coincident with downregulation of PTH/PTHrP receptor mRNA expression. In situ hybridization and immunohistochemistry revealed that PTHrP expression in balloon-denuded carotid arteries was mainly localized to the neointima. To confirm the involvement of the PTHrP in human coronary artery restenotic lesions, immunohistochemical analysis of human coronary atherectomy specimens (23 primary and 10 restenotic lesions) was then performed. The number of intimal cells that expressed PTHrP protein was significantly higher in restenotic than in stable angina or unstable angina specimens. These data demonstrate that PTHrP gene expression in VSMCs markedly increases during neointimal formation, supporting the hypothesis that PTHrP may play an important role in vascular stenosis as a regulator of VSMC proliferation.