Abstract
Vascular endothelial growth factor (VEGF)-D, a member of the VEGF family, induces both angiogenesis and lymphangiogenesis by activating VEGF receptor-2 (VEGFR-2) and VEGFR-3 on the surface of endothelial cells. Transforming growth factor (TGF)-β1 has been shown to stimulate VEGF-A expression in human lung fibroblast via the Smad3 signaling pathway and to induce VEGF-C in human proximal tubular epithelial cells. However, the effects of TGF-β1 on VEGF-D regulation are unknown. To investigate the regulation of VEGF-D, human lung fibroblasts were studied under pro-fibrotic conditions in vitro and in idiopathic pulmonary fibrosis (IPF) lung tissue. We demonstrate that TGF-β1 downregulates VEGF-D expression in a dose- and time-dependent manner in human lung fibroblasts. This TGF-β1 effect can be abolished by inhibitors of TGF-β type I receptor kinase and Jun NH2-terminal kinase (JNK), but not by Smad3 knockdown. In addition, VEGF-D knockdown in human lung fibroblasts induces G1/S transition and promotes cell proliferation. Importantly, VEGF-D protein expression is decreased in lung homogenates from IPF patients compared with control lung. In IPF lung sections, fibroblastic foci show very weak VEGF-D immunoreactivity, whereas VEGF-D is abundantly expressed within alveolar interstitial cells in control lung. Taken together, our data identify a novel mechanism for downstream signal transduction induced by TGF-β1 in lung fibroblasts, through which they may mediate tissue remodeling in IPF.
Highlights
Vascular endothelial growth factors (VEGFs) contribute to physiological and pathological angiogenesis and lymphangiogenesis during embryonic development and adult life [1]
To examine the downstream signaling molecules that mediate the effect of Transforming growth factor (TGF)-β1 on VEGF-D transcription, MRC-5 cells were pretreated with selective inhibitors of activin receptor–like kinase (ALK)-5 (SB431542, 10 μmol/L [inhibitors and amounts given in parentheses in this sentence]) (R&D Systems), mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) (UO126, 10 μmol/L) (Cell Signaling Technology, Danvers, MA, USA), phosphatidylinositol 3-kinase (PI3K)/Akt (Cell Signaling Technology), Jun NH2-terminal kinase (JNK) (SP600125, 5 μmol/L) (Cell Signaling Technology) or p38 mitogenactivated protein kinase (p38MAPK) (SB203580, 10 μmol/L) (R&D Systems) 1 h before the addition of TGF-β1
TGF-β1 transiently upregulated both VEGF-A and VEGF-C expression, both of which peaked at 8 h and declined toward baseline values thereafter
Summary
Vascular endothelial growth factors (VEGFs) contribute to physiological and pathological angiogenesis and lymphangiogenesis during embryonic development and adult life [1]. Six members of the VEGF family have been identified: VEGF-A, -B, -C, -D and -E and placenta growth factor [2]. VEGF family members are structurally and functionally related, they possess distinct receptor binding specificities that contribute to their diversity of function [3,4]. Among the six members discovered to date, VEGF-A is the most comprehensively characterized cytokine. It is a major contributor to angiogenesis and regulates multiple endothelial cell functions via VEGF receptors (VEGFRs) 1 and 2 [5]. VEGF-C and -D, on the other hand, form a functional subgroup that primarily mediates lymphangiogenesis via VEGFR-3 and angiogenesis via VEGFR-2 [6]
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