Abundant expression of parathyroid hormone-related protein in primary rat aortic smooth muscle cells accompanies serum-induced proliferation.

Abstract

Parathyroid hormone-related protein (PTHrP), which is responsible for producing hypercalcemia in patients with humoral hypercalcemia of malignancy, has recently been identified in several normal tissues. Because PTHrP, like parathyroid hormone (PTH), is known to exhibit vasodilatory properties, we investigated the expression and regulation of PTHrP mRNA in cultured rat aortic smooth muscle cells (SMC). We report here that PTHrP mRNA is expressed in SMC and is markedly induced by serum in a time-and concentration-dependent fashion. Addition of 10% fetal calf serum to serum-deprived, confluent cells, resulted in a marked induction of PTHrP mRNA by 2 h with a peak at 4-6 h. PTHrP was detected in SMC by immunocytochemistry and radioimmunoassay of conditioned medium, and was shown to be up-regulated within 24 h after the addition of serum. The serum induction of PTHrP mRNA was blocked by actinomycin D and by cycloheximide indicating the need for protein synthesis to evoke the serum effect on PTHrP gene transcription. In addition, treatment with dexamethasone, which has been previously shown to reduce the constitutive expression of PTHrP in human cancer cells, also blunted the serum induction of PTHrP mRNA in SMC. Treatment of quiescent cells with the serum mitogens platelet-derived growth factor or insulin-like growth factor-I had no effect on PTHrP, whereas the vasoactive peptides endothelin, norepinephrine and thrombin stimulated PTHrP expression. Exogenous addition of recombinant had no significant effect on SMC DNA synthesis as measured by [3HJthymidine incorporation. In summary, the abundance of PTHrP mRNA and the characteristics of its regulation in SMC suggest a major role for PTHrP as a local modulator in vascular smooth muscle. (J. Clin. Invest. 1991. 88:1841-1847

Parathyroid hormone-like protein is a secretory product of atrial myocytes.

“…A stretch signal for increased PLP production, well documented for smooth muscle, may also be present in heart muscle (26)(27)(28)(29)(30). In preliminary studies, we have demonstrated an increased concentration of PLP in the stretched, failing rat heart; however we have not as yet been able to identify a secretagogue for PLP (unpublished observations of the authors).…”

Targeted Overexpression of Parathyroid Hormone-Related Protein (PTHrP) to Vascular Smooth Muscle in Transgenic Mice Lowers Blood Pressure and Alters Vascular Contractility

“…Northern blots were performed as previously described (13). Briefly, 20 g tissue total RNA were gel separated, transferred to a Nylon membrane, and then hybridized with random primed human PTHrP cDNA.…”

“…Exogenous application of synthetic PTHrP peptides exert relaxant activity on both conductance and resistance vessels from different species (12). Cultured arterial vascular smooth muscle cells express both PTHrP (13) and the type 1 PTH/PTHrP receptor (14). In addition, PTHrP production by cultured vascular smooth muscle cells is stimulated by vasoconstrictor agents such as angiotensin II (15), suggesting the existence of a short feedback loop through which the local vasorelaxant actions of PTHrP function to oppose pressor activity of angiotensin II and other vasoconstrictor agents.…”

Vitamin D3 differentially regulates parathyroid hormone/parathyroid hormone-related peptide receptor expression in bone and cartilage

“…PTH-related peptide (PTHrP) was first identified as a factor that mimics the action of PTH when overexpressed by a number of tumors (9)(10)(11)(12). PTHrP is important for normal skeletal development (13)(14)(15)(16)(17) and stimulates differentiation of a number of cell types (18)(19)(20)(21)(22)(23), in addition to other physiological functions (24)(25)(26)(27)(28). In contrast to PTH, PTHrP is widely expressed both in the fetus and the adult and acts in a paracrine or autocrine manner under physiological conditions (29)(30)(31).…”