Mechanical force regulation of vascular parathyroid hormone-related peptide expression

Parathyroid hormone-related peptide (PTHrP) was originally identified as a factor responsible for the syndrome of humoral hypercalcemia of malignancy. PTHrP has a vasodilator activity and is produced in vascular smooth muscle. However, the exact physiological role of PTHrP and the regulation of its gene expression in the vascular system have not been understood. We found that the mechanical stretch of rat aortic smooth muscle cells in vitro induced a marked increase in PTHrP expression through a protein kinase C-dependent mechanism. We further examined whether PTHrP expression in blood vessels in vivo is regulated by mechanical forces. Mechanical stretch of isolated aortic strips increased the expression of PTHrP mRNA. The PTHrP mRNA expression levels in aortae from hypertensive 18-week-old spontaneously hypertensive rats (SHR) was twofold higher than age-matched control Wistar-Kyoto (WKY) rats, while the PTHrP mRNA level in the aortae from normotensive 4-week-old SHR was not different from that of age-matched control WKY rats. Moreover, treatment of hypertensive SHR with an angiotensin II type 1 receptor antagonist or hydralazine caused a decrease in PTHrP expression in the aortae with the lowering of blood pressure. These results indicate that the gene expression of the vasoleraxant PTHrP in blood vessels is under the regulation of mechanical forces, and suggest a modulatory role for PTHrP in the regulation of vascular tone.