1a,25(OH)2D3 regulates pro-angiogenic factors in endothelial cells transformed by Kaposi's sarcoma-associated herpesvirus G protein coupled receptor

When tumoral cell expansion exceeds the vascular supply, regions of hypoxia or low oxygen concen-tration are generated promoting the formation of new vessels through cell proliferation and migration. Viral G protein-coupled receptor (vGPCR) is associated to Kaposi's sarcoma pathology and induces a paracrine transformation when is stably expressed in murine endothelial cells activating hypoxia-induced transcription factors. Previously, we reported the antiproliferative actions of 1a,25-dihydroxyvitamin D3 (1a,25(OH)2D3) in endothelial cells transformed by the vGPCR (SVEC-vGPCR). Herein, we further investigated if pro-angiogenic factors as AP-1, HIF-1a and VEGF are modulated by 1a,25(OH)2D3. We found by qRT-PCR analysis that the mRNA level of JunB, a negative regulator of cell proliferation, was similarly increased at all-time points tested after 1a,25(OH)2D3 treatment in SVEC-vGPCR cells. Also, mRNA levels of the pro-angiogenic factor c-Fos, which induces tumor invasion, were only decreased during one short period treatment. In addition, Hif-1a mRNA and protein levels were significantly reduced after 1a,25(OH)2D3 treatment in a VDR dependent fashion. However, mRNA levels of the angiogenic activator Vegf, promoted in turn by Hif-1a expression, were surprisingly high depending on VDR expression as well. Moreover, Egr-1, which has been reported to induce VEGF expression independently of HIF-1a, diminished its expression with 1a,25(OH)2D3 treatment, fact that was related to the decline of p-ERK1/2. Altogether, these results suggest a negative modulation of some pro-angiogenic factors like AP-1 and HIF-1a, as part of the antiproliferative mechanism of 1a,25(OH)2D3 in SVEC-vGPCR endothelial cells. (c) 2023 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved.