Endothelial HNF4α potentiates angiogenic dysfunction via enhancement of vascular endothelial growth factor resistance in T2DM
| Autor: | Yaya Gao, Jing Jin, Xubing Chai, Jun Yan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Vascular Endothelial Growth Factor A p38 mitogen-activated protein kinases Drug Resistance Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Thrombin Downregulation and upregulation Cell Movement medicine Human Umbilical Vein Endothelial Cells Animals Humans Protein kinase A Molecular Biology Protein kinase B Cells Cultured Cell Proliferation Tube formation Base Sequence Kinase Chemistry Cell Biology Vascular endothelial growth factor Mice Inbred C57BL 030104 developmental biology Diabetes Mellitus Type 2 Gene Expression Regulation Hepatocyte Nuclear Factor 4 030220 oncology & carcinogenesis Cancer research Blood Vessels medicine.drug Signal Transduction |
| Zdroj: | Journal of cellular biochemistry. 120(8) |
| ISSN: | 1097-4644 |
| Popis: | Although both hyperprocoagulant status, characterized by elevated thrombin levels, and vascular endothelial growth factor (VEGF) resistance, marked by attenuated expression of VEGFR2 (also called FLK1 or KDR), are known to contribute importantly to an increased risk of vascular events in diabetes mellitus type 2 (T2DM), it remains obscure whether these two biological events regulate angiogenic response in a coordinated manner. We show here that endothelial expression of hepatocyte nuclear factor 4α (HNF4α) was significantly upregulated in rodents and humans with T2DM, and HNF4α upregulation by thrombin was dependent on activation of multiple pathways, including protein kinase B, c-Jun N-terminal kinase, p38, oxidative stress, protein kinase C, and AMPK (5'-adenosine monophosphate (AMP)-activated protein kinase). Functionally, HNF4α inhibited VEGF-mediated endothelial proliferation and migration, and blunted VEGF-stimulated in vitro angiogenesis, thus rendering endothelial cells unresponsive to established angiogenic VEGF stimulation. Mechanistically, HNF4α potentiated the endothelial VEGF resistance through the direct transcriptional repression of FLK1 gene. From a therapeutic standpoint, overexpression of the exogenous FLK1 successfully rescued HNF4α-inhibited angiogenic response to VEGF and potentiated VEGF-stimulated in vitro tube formation. Considering a strong association between HNF4A deregulation and increased risk of T2DM, our findings suggest that HNF4α may act as a critical converging point linking hyperprocoagulant condition to VEGF resistance in diabetic ECs, and repression of FLK1 expression by thrombin-induced HNF4α mediates, at least partially, the vascular dysfunction caused by T2DM. |
| Databáze: | OpenAIRE |
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