Reduced blood pressure and increased sensitivity of the vasculature to parathyroid hormone-related protein (PTHrP) in transgenic mice overexpressing the PTH/ PTHrP receptor in vascular smooth muscle

PTH-related protein (PTHrP) is produced in vascular smooth muscle, where it is postulated to exert vasorelaxant properties by activation of the PTH/PT HrP type 1 receptor. As a model for studying the actions of locally produce d PTHrP in vascular smooth muscle in vivo, we developed transgenic mice tha t overexpress the PTH/PTHrP receptor (PTHrP-R) in smooth muscle. Oocyte inj ection with a SMP8-PTHrP-R fusion construct yielded six founder mice. F-1 o ffspring were viable and demonstrated selective overexpression of the SMP8- PTHP-R messenger RNA in smooth muscle-rich tissues. Baseline blood pressure measured in conscious mice by tail sphygmomanometry was significantly lowe r in the receptor-overexpressing mice than that in controls (117 +/- 4 vs. 133 +/- 3 mm Hg; P < 0.05). In anesthetized animals, iv infusion of PTHrP-( 1-34)NH2 caused a significantly greater reduction in blood pressure and tot al peripheral resistance in transgenic mice than in control animals. Vascul ar contractility was studied in paired, isometrically mounted aortas from 9 -week-old transgenic and wild-type mice. The force of contraction in respon se to phenlyephrine was not significantly different between transgenic and wild-type mice. However, PTHrP-(1-34) NH2 relaxed aortic vessel preparation s from transgenic mice to a greater extent than in controls (77.1 +/- 3% vs . 38.4 +/- 4%; P < 0.001). To determine the impact of overexpression of PTH /PTHrP type 1 receptor and its ligand on the development of the cardiovascu lar system, double transgenic mice were created by crossing SMP8-PTHrP-R tr ansgenic mice with mice overexpressing PTHrP (SMP8-PTHrP). Double transgeni c mice died around day E9 with abnormalities in the developing heart. In co nclusion, overexpression of PTH/PTHrP type 1 receptor in vascular smooth mu scle of transgenic mice reduces blood pressure, probably through sustained activation of the receptor by endogenous ligand. The cardiovascular defects observed in mice overexpressing both PTHrP and its receptor suggest that P THrP may play a role in the normal development of the cardiovascular system .