Parathyroid-hormone-related protein (PTHrP) regulates proliferation in vascular smooth muscle cells (VSM) in a bi-directional fashion

T. Massfelder, S. Khosravi, T. Wu, J. J. Helwig, A. F. Stewart

Research output: Contribution to journalArticlepeer-review

Abstract

PTHrP is a prohormone which gives rise to (1-36), (38-94) and (107-139) secretory forms. It is produced in VSM, is a potent vasodilator, and is upregulated by mechanical stretch and by arterial injury. PTHrP receptors coupled to cAMP and NO are present on VSM. In addition to receptor-mediated effects of PTHrP, nuclear targeting of PTHrP appears to occur in keratinocytes and chondrocytes. and to be mediated by basic nuclear localization sequences (NLS). To determine whether cell surface receptor-mediated mitogenic effects of PTHrP differ from those due to nuclear targeting in VSM, we compared responses inVSM to PTHrP either added exugenously to medium or introduced by stable transfection. Exposure of A10 (rat) and bovine aortic VSM to PTHrP(1-36) yielded dose-dependent inhibition of proliferation (25-40%. IC50) = 1 nM). PTHrP(38-94) and (107-139) had no effect. In marked contrast, stable expression of PTHrP yielded 3-fold stimulation of proliferation. Immunocytochemistry demonstrated nuclear localization of PTHrP in A-10 cells. To define whether these effects were specific to PTHrP, parathyroid hormone (PTH), which lacks an NLS, was studied. In contrast to PTHrP, whether added to medium or by transfection, PTH inhibited proliferation. PTHrP is a locally-produced vasoregulatory peptide. In addition to its potent vasodilatory properties, PTHrP has dual effects on VSM proliferation, consistent with opposing paracrine receptor-dependent and "intracrine" nuclear effects. Deletion/mutation of the PTHrP NLS is in progress.

Original languageEnglish
Pages (from-to)A197
JournalFASEB Journal
Volume11
Issue number3
StatePublished - 1997

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