1,25-dihydroxyvitamin D3 modulates growth of vascular smooth muscle cells.

Abstract

We examined the effects of 1,25-dihydroxyvitamin D3(1,25-(OH)2D3) on the proliferation of vascular smooth muscle (VSM) cells. Receptors for 1,250-H)2D3 were demonstrated in fresh rabbit aortic tissue and in cultured rat VSM using binding of 13H1-1,25-0H)2D3 in sucrose density gradients of the tissue or cell homogenates. The receptor sedimented at 3.6 S, the sedimentation velocity of 1,2501H)2D3 receptors from other sources. 1,2540H)2D3 dramatically altered the growth of VSM, but this effect depended importantly on the basal conditions in which the cells were grown. In quiescent VSM deprived of serum for 72 h, 1,2540H)2D3 (0.1-10 nM), but not 25-(OH)D3 (up to 100 nM) increased thymidine incorporation up to 12-fold and cell number up to 2.6-fold compared with controls. The maximal effect of 1,25-(0H)D3 on thymidine incorporation was similar to the maximal effect of the growth factors a-thrombin or PDGF. Furthermore, the effects of 1,25-(OH)2D3 and thrombin on thymidine incorporation in quiescent cells were markedly synergistic, yielding a 78-fold increase in thymidine incorporation when both agents were added simultaneously. In "nonquiescent cells" which were exposed to serumfree medium for only 24 h, 1,2540H)2D3 (10 nM) also increased DNA synthesis 10-fold compared with controls. However, in striking contrast to what was observed in quiescent cells, 1,25-(OH)2D3 diminished the mitogenic response to thrombin by as much as 50% in nonquiescent cells. 1,25-(OHh)D3 also modulated the transcription of c-myc in response to thrombin. In quiescent cells, transcription was enhanced by 1,25-(OH)2D3, whereas in nonquiescent cells, thrombin-induced c-myc transcription was blunted. Thus, 1,25-(0H)2D3 is a potent modulator of the growth of cultured VSM. The direction of this modulation depends strongly on the conditions under which the cells are cultured. (J. Clin. Invest. 1991.

Arterial diffuse intimal thickening associated with enzootic calcinosis of sheep

“…VDR s which are DNA-linked proteins (Mitsuhashi et al 1991) were identified in SMCs in vitro (Kawashima 1987, Merke et al1987, Koh et al 1988. Stimulation of these receptors induce cell proliferation and differentiation in several tissues (Pike 1985, Pols et al 1990, Walters 1992, and there is an increase in DNA synthesis and a decrease in heparan sulfate, a glycosaminoglycan responsible for the inhibition of the proliferation of these cells, allowing multiplication of the SMCs (Koh et al 1990).…”

Associations between vitamin D receptor genotypes and mortality in a cohort of older Dutch individuals

“…Vitamin D exerts its action at a cellular level through binding of the active metabolite 1,25-dihydroxyvitamin D to the vitamin D receptor (VDR). The VDR is expressed in many different cell types such as pancreatic b cells (1), vascular smooth muscle cells (2), and osteoblasts and chondrocytes (3). Several polymorphisms in the gene encoding the VDR, such as Cdx2, FokI, BsmI, ApaI, and TaqI, have been demonstrated to be related to bone characteristics and risk of fractures, although results remain equivocal (4)(5)(6).…”

25-Hydroxyvitamin D 3 -1α-Hydroxylase Is Expressed in Human Vascular Smooth Muscle Cells and Is Upregulated by Parathyroid Hormone and Estrogenic Compounds

“…Both endothelial cells and vascular smooth muscle cells (VSMCs) express high-affinity receptors for 1,25(OH) 2 vitamin D 3 , 1,2 and vitamin D metabolites exert numerous effects in VSMCs [3][4][5][6][7][8][9][10] that involve vital aspects of VSMC function and pathology, including contractility, growth and migration, and the evolution of vascular calcifications. Vitamin D metabolites appear to enhance the expression of Ca-ATPase, 3 increase the entry of calcium into the cell, 4 raise cytosolic free calcium, 5 induce the expression of contractile proteins, 6 and accelerate the formation of prostacyclin 7 in VSMCs, all of which may directly or indirectly affect arterial tone.…”

“…Vitamin D metabolites appear to enhance the expression of Ca-ATPase, 3 increase the entry of calcium into the cell, 4 raise cytosolic free calcium, 5 induce the expression of contractile proteins, 6 and accelerate the formation of prostacyclin 7 in VSMCs, all of which may directly or indirectly affect arterial tone. Evidence also suggests that 1,25(OH) 2 vitamin D 3 inhibits VSMC replication 8,9 and diminishes the mitogenic response to growth enhancers such as thrombin or platelet-derived growth factor (PDGF). 9 On the other hand, 1,25(OH) 2 vitamin D 3 may accelerate cell migration 10 and promote the transition of contractile VSMCs into a secretory cell phenotype.…”

“…Evidence also suggests that 1,25(OH) 2 vitamin D 3 inhibits VSMC replication 8,9 and diminishes the mitogenic response to growth enhancers such as thrombin or platelet-derived growth factor (PDGF). 9 On the other hand, 1,25(OH) 2 vitamin D 3 may accelerate cell migration 10 and promote the transition of contractile VSMCs into a secretory cell phenotype. 11 Finally, 1,25(OH) 2 D 3 has been linked to the formation of arterial calcifications in a complex and poorly understood manner; although hypervitaminosis D induces vascular calcifications 12,13 and 1,25(OH) 2 vitamin D 3 increases the expression of bone proteins such as osteopontin in VSMCs, 10,13 coronary calcifications appear to be inversely related to circulating 1,25(OH) 2 vitamin D 3 .…”