All-trans Retinoic Acid Induces in Vitro Angiogenesis via Retinoic Acid Receptor: Possible Involvement of Paracrine Effects of Endogenous Vascular Endothelial Growth Factor Signaling

Abstract

A natural retinoid all-trans retinoic acid (ATRA) regulates a variety of important cellular functions via retinoic acid receptor (RAR). ATRA has therapeutically been used against various malignancies including acute promyelocytic leukemia. Recently ATRA has also been recognized to be beneficial against atherosclerotic vascular disorders. However, its effects on angiogenesis remain controversial. We therefore examined ATRA effects on in vitro angiogenesis in terms of capillary-like tube formation using human umbilical vein endothelial cells (HUVECs)/normal human dermal fibroblast (NHDF) coculture. ATRA as well as RAR agonist Am80 significantly induced capillary-like tube formation. The ATRA-induced tube formation was inhibited by coincubation with RAR antagonist LE540/LE135. HUVEC proliferation, but not its migration, was also induced by ATRA. The ATRA-induced tube formation was completely abolished by coincubation with vascular endothelial growth factor (VEGF) neutralizing antibody or with VEGF receptor (VEGFR)-2 (KDR) neutralizing antibody, but not VEGFR-1 (Flt-1) neutralizing antibody. ATRA and Am80 induced VEGF secretion in the coculture as well as VEGF secretion/mRNA expression in NHDFs. Transcription activity of human VEGF gene promoter in NHDFs was stimulated by ATRA, which was augmented by RAR overexpression. ATRA also induced VDGFR-2/KDR mRNA expression in HUVECs. Moreover, ATRA-induced secretion of hepatocyte growth factor as well as angiopoietin-2 in the coculture. Taken together, ATRA may have induced angiogenesis via RAR mainly by stimulation of HUVEC proliferation and enhancement of endogenous VEGF signaling and in part by induction of hepatocyte growth factor and angiopoietin-2 production. Retinoids may therefore be potential candidates for therapeutic angiogenesis against ischemic vascular disorders.

The MicroRNA miR-199a-5p Down-regulation Switches on Wound Angiogenesis by Derepressing the v-ets Erythroblastosis Virus E26 Oncogene Homolog 1-Matrix Metalloproteinase-1 Pathway

“…Hydrogen peroxide, a well known pro-angiogenic stimulus (44,45), activates nuclear factor (erythroid-derived 2)-like 2, leading to binding to antioxidant response elements and subsequent enhancement of Ets-1 promoter activity (46). Retinoic acid induces angiogenesis (47), with concomitant induction of Ets-1 transactivation (48). The findings from the current investigation, which agree with our previously published work (3), suggest an additional mechanism: Ets-1 expression is regulated through post-transcriptional modification in response to angiogenic stimulation.…”

Acyclic retinoid inhibits angiogenesis by suppressing the MAPK pathway

“…This might be because of the induction of VEGF by atRA as reported previously. 17 ACR did not affect the levels of VEGF mRNA and the transactivation of the VEGF promoter (data not shown). ACR slightly inhibited the phosphorylation of VEGFR1 at 300 mM but not at all at 30 mM (Ishibashi et al, unpublished data).…”

β-Cryptoxanthin Suppresses the Adipogenesis of 3T3-L1 Cells via RAR Activation

“…To confirm whether ␤-cryptoxanthin affects 3T3-L1 differentiation via RAR␣ and ␥ activation, we assessed the effects of ␤-cryptoxanthin in the presence of LE540, an RAR pan-antagonist (15). As shown in Fig.…”