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(Circulation Research. 2006;99:933.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Cellular Mechanism Through Which Parathyroid Hormone–Related Protein Induces Proliferation in Arterial Smooth Muscle Cells

Definition of an Arterial Smooth Muscle PTHrP/p27^kip1 Pathway

Nathalie Fiaschi-Taesch, Brian M. Sicari, Kiran Ubriani, Todd Bigatel, Karen K. Takane, Irene Cozar-Castellano, Alessandro Bisello, Brian Law, Andrew F. Stewart

From the Division of Endocrinology (N.F.-T., B.M.S., K.U., T.B., K.K.T., I.C.-C., A.B., A.F.S.), University of Pittsburgh School of Medicine, Pa; and Department of Pharmacology and Experimental Therapeutics (B.L.), University of Florida, Gainesville.

Correspondence to Nathalie Fiaschi-Taesch, PhD, Instructor, Division of Endocrinology and Metabolism, BST E-1140, Endocrinology, University of Pittsburgh School of Medicine, 3550 Terrace St, Pittsburgh, PA 15213. E-mail Taeschn{at}msx.dept-med.pitt.edu

Parathyroid hormone–related protein (PTHrP) is present in vascular smooth muscle (VSM), is markedly upregulated in response to arterial injury, is essential for normal VSM proliferation, and also markedly accentuates neointima formation following rat carotid angioplasty. PTHrP contains a nuclear localization signal (NLS) through which it enters the nucleus and leads to marked increases in retinoblastoma protein (pRb) phosphorylation and cell cycle progression. Our goal was to define key cell cycle molecules upstream of pRb that mediate cell cycle acceleration induced by PTHrP. The cyclin D/cdk-4,-6 system and its upstream regulators, the inhibitory kinases (INKs), are not appreciably influenced by PTHrP. In striking contrast, cyclin E/cdk-2 kinase activity is markedly increased by PTHrP, and this is a result of a specific, marked, PTHrP-induced proteasomal degradation of p27^kip1. Adenoviral restoration of p27^kip1 fully reverses PTHrP-induced cell cycle progression, indicating that PTHrP mediates its cell cycle acceleration in VSM via p27^kip1. In confirmation, adenoviral delivery of PTHrP to murine primary vascular smooth muscle cells (VSMCs) significantly decreases p27^kip1 expression and accelerates cell cycle progression. p27^kip1 is well known to be a central cell cycle regulatory molecule involved in both normal and pathological VSM proliferation and is a target of widely used drug-eluting stents. The current observations define a novel "PTHrP/p27^kip1 pathway" in the arterial wall and suggest that this pathway is important in normal arterial biology and a potential target for therapeutic manipulation of the arterial response to injury.

Key Words: cell cycle progression • p27Kip1/pRb • proliferation • PTHrP • vascular smooth muscle cell proliferation