4.5 Article

TGF-1 inhibits microvascular-like formation by decreasing VCAM1 and ICAM1 via the upregulation of SNAIL in human granulosa cells

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ELSEVIER IRELAND LTD
DOI: 10.1016/j.mce.2021.111395

关键词

Granulosa cell; TGF-beta 1; SNAIL; VCAM1; ICAM1; Angiogenesis

资金

  1. CIHR Foundation Scheme [143317]
  2. National Science Foundation of China [31601943]
  3. Natural Science Foundation of Jiangsu Province [BK20151365]
  4. Na-tional Science and Technology Major Project of China [2016ZX08006003]

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This study suggests that TGF-beta 1 may upregulate the expression of SNAIL transcription factor, leading to a suppression of VCAM1 and ICAM1 in hGL cells, thereby inhibiting granulosa cell angiogenesis. The inhibitory effects of TGF-beta 1 on VCAM1 and ICAM1 expression may be mediated through an ALK5-dependent SMAD signaling pathway.
Three major endothelial cell junctional adhesion molecules (VCAM1, ICAM1 and E-SELECTIN) play important roles in the process of angiogenesis, a progression of extensive physiological vascularization that occurs during the formation of the corpus luteum. Our previous studies demonstrated that TGF-beta 1 is a negative regulator of luteinization and progesterone production in luteinized human granulosa (hGL) cells. Whether TGF-beta 1 can regulate the expression of these endothelial cell adhesion molecules and subsequent angiogenesis in hGL cells remains to be elucidated. Using dual inhibition approaches (small molecular inhibitors and siRNA-based knockdown), we provided the first data showing that TGF-beta 1 significantly upregulates the expression of the SNAIL transcription factor, which in turn suppresses the expression of VCAM1 and ICAM1 in hGL cells. Additionally, we demonstrate that the suppressive effects on the expression of VCAM1 and ICAM1 induced by TGF-beta 1 treatment were most likely via an ALK5-mediated SMAD-dependent signaling pathway. Furthermore, functional studies showed that hGL cells cultured on Matrigel exhibited two typical endothelial cell phenotypes, microvascular-like formation and a sprouting microvascular pattern. Notably, these phenotypes were significantly suppressed by either TGF-beta 1 treatment or knockdown of VCAM1 and ICAM1. Our findings suggest that TGF-beta 1 plays a potential role in the inhibition of granulosa cell angiogenesis by downregulating the expression of VCAM1 and ICAM1 during follicular development and corpus luteum formation.

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