Low levels of 25-hydroxyvitamin D3 have been associated with hypertension, peripheral vascular disease and congestive heart failure. In animal studies, vitamin D deficiency leads to hypertension, and vitamin D receptor (VDR) knockout mice develop hyperreninemic hypertension and cardiac hypertrophy. Collectively, these data suggest that vitamin D possesses significant vasculoprotective effects in animals and humans. 1,25- dihydroxyvitamin D3 (VD3) and its analogues have been shown to effectively inhibit proliferation of cancer cells in vitro and in vivo, especially in tissues with high levels of expression of endogenous VDR, such as breast and prostate. Some VD3 analogues suppress cancer growth in animal models and humans without development of hypercalcemia. [Although VD3 has been shown to have effects on various cell cycle regulators in cell type- specific fashion, the precise target for VD3 inhibition has not been found]. Our preliminary data and those of others indicate that VD3 and its analogues suppress mitogen-induced proliferation of cultured vascular smooth muscle cells (VSMC), but the mechanism is unknown. We show here that VD3 and its analogues inhibit endothelin (ET)-stimulated mitogenesis and that the inhibition is linked to a reduction in the activity of the G1 gatekeeper kinase, Cdk2. This reduction is mediated by inhibition of ET-induced transcription of Cdc25A gene in adult rat VSMC. [These results suggest that VD3 and its analogues have the capacity to effectively inhibit aberrant VSMC proliferation through suppression of Cdc25A gene transcription. To test this hypothesis,] we will first identify the loci on the rat Cdc25A promoter that mediates VD3-dependent inhibition of Cdc25A gene transcription. Second, [we will examine the effects of the non-hypercalcelmic VD3 analogue, Ro 25-6760, on the VSMC proliferative response in injured rat carotid arteries and determine whether this inhibition is linked to occupancy of the endogenous Cdc25A gene promoter by the liganded VDR]. Finally, using a VDR knockout mouse that we created through deletion of a loxp-bordered exon 4 in the VDR gene, we will determine whether VDR deficiency accelerates neointimal and medial hyperplasia following carotid artery injury, and whether this is linked to increased Cdc25A gene expression. The proposed studies will provide novel insight into the molecular mechanism(s) governing VD3-dependent inhibition of VSMC proliferation and provide direct evidence for the potential utility of VD3 analogues in the prevention and treatment of vasculopathic disorders, like hypertension, atherosclerosis, transplant vasculopathy, re-stenosis post-angioplasty and vein bypass graft failure, which are associated with aberrant VSMC proliferation and remodeling in the vessel wall.

Public Health Relevance

Aberrant vascular smooth muscle cell (VSMC) growth plays a pivotal role in the pathogenesis of chronic vascular disease, e.g. atherosclerosis and hypertension, and in subacute vascular injury, as seen in transplant vasculopathy, in-stent stenosis and vein bypass graft failure. Research outlined in this proposal will seek to generate evidence that VD3 analogues suppress abnormal VSMC growth in an animal model and help to substantiate the hypothesis that vitamin D sufficiency is important for maintenance of vascular health.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL096047-02
Application #
8011336
Study Section
Special Emphasis Panel (ZRG1-CVS-Q (90))
Program Officer
Reid, Diane M
Project Start
2010-01-15
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2011
Total Cost
$193,125
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Chen, Songcang; Villalta, S Armando; Agrawal, Devendra K (2016) FOXO1 Mediates Vitamin D Deficiency-Induced Insulin Resistance in Skeletal Muscle. J Bone Miner Res 31:585-95
Chen, Songcang; Sun, Yingxian; Agrawal, Devendra K (2015) Vitamin D deficiency and essential hypertension. J Am Soc Hypertens 9:885-901
Gardner, David G; Chen, Songcang; Glenn, Denis J (2013) Vitamin D and the heart. Am J Physiol Regul Integr Comp Physiol 305:R969-77
Chen, Songcang (2012) Essential hypertension: perspectives and future directions. J Hypertens 30:42-5
Chen, Songcang; Law, Christopher S; Grigsby, Christopher L et al. (2011) Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation 124:1838-47
Chen, Songcang; Law, Christopher S; Grigsby, Christopher L et al. (2010) A role for the cell cycle phosphatase Cdc25a in vitamin D-dependent inhibition of adult rat vascular smooth muscle cell proliferation. J Steroid Biochem Mol Biol 122:326-32