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Evidence That Implicates the Parathyroid Hormone–Related Peptide in Vascular Stenosis
Increased Gene Expression in the Intima of Injured Rat Carotid Arteries and Human Restenotic Coronary Lesions
From the Third Department of Internal Medicine (S.O., S.S., S.T., K.Y.) and the Departments of Cell Physiology (A.O., H.Y., S.Y.) and Pathology (T.N., M.I.), Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, and the Kokura Memorial Hospital, Kitakyushu (T.Y., M.N.), Japan; and the Endocrine Unit, Massachusetts General Hospital, Boston, Mass (G.V.S.).
Correspondence to Akira Ohtsuru, MD, Department of Cell Physiology, Atomic Disease Institute, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852, Japan.
Abstract 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 (407±53 cells/mm2; range, 143 to 739) than in stable angina (50±12 cells/mm2; range, 18 to 132; P<.05) or unstable angina (129±16 cells/mm2; range, 21 to 232; P<.05) 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.
Key Words: PTH/PTHrP receptor • restenosis • atherectomy • neointimal formation • PTHrP
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