Raquel Costa1,2, Ilda Rodrigues1, Luísa Guardão3, Joana Quelhas Lima4, Emília Sousa4,5, Raquel Soares1,2, Rita Negrão1,2. 1. Department of Biochemistry, Faculty of Medicine of the University of Porto, Porto, Portugal. 2. i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. 3. Animal Facility, Faculty of Medicine of the University of Porto, Porto, Portugal. 4. Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, FFUP - Faculty of Pharmacy, University of Porto, Porto, Portugal. 5. CIIMAR/CIMAR - Interdisciplinary Center of Marine and Environmental Research, University of Porto, Porto, Portugal.
Abstract
SCOPE: Imbalance in kidney and heart neovascularization is common in type2 diabetes (T2DM) patients. Nevertheless, the mechanisms governing this angiogenic paradox have not been elucidated. Xanthohumol (XN) and 8-prenylnaringenin (8PN) beer polyphenols modulate angiogenesis, being thus targets for T2DM-related complications. Our work examined whether polyphenols consumption affects angiogenic paradox and metabolism in a T2DM mouse model. METHODS AND RESULTS: An increase in kidney and a reduction in left ventricle (LV) microvessels of diabetic C57Bl/6 mice were observed. XN consumption reduced angiogenesis, VEGFR-2 expression/activity, VEGF-A and phosphofructokinase-2/fructose-2,6-bisphosphatase-3 enzyme expression, a metabolic marker present in endothelial tip cells in T2DM mice kidney. 8PN had opposite effects in T2DM mice LV. These XN and 8PN effects were dependent on VEGF levels as revealed by in vitro assays. These findings were accompanied by tissue and plasma reduced expression levels of VEGF-B and its receptors, VEGFR1 and neuropilin-1, by both polyphenols. CONCLUSION: Beer polyphenols modulate T2DM angiogenic paradox in a tissue-dependent manner. We also show for the first time that both polyphenols decreased VEGF-B pathway, which is implicated in endothelial-to-tissue lipid metabolism. Altogether, the effects of these polyphenols in the crosstalk between angiogenesis and metabolism render them potent agents for novel diabetic therapeutic interventions.
SCOPE: Imbalance in kidney and heart neovascularization is common in type2 diabetes (T2DM) patients. Nevertheless, the mechanisms governing this angiogenic paradox have not been elucidated. Xanthohumol (XN) and 8-prenylnaringenin (8PN) beer polyphenols modulate angiogenesis, being thus targets for T2DM-related complications. Our work examined whether polyphenols consumption affects angiogenic paradox and metabolism in a T2DM mouse model. METHODS AND RESULTS: An increase in kidney and a reduction in left ventricle (LV) microvessels of diabetic C57Bl/6 mice were observed. XN consumption reduced angiogenesis, VEGFR-2 expression/activity, VEGF-A and phosphofructokinase-2/fructose-2,6-bisphosphatase-3 enzyme expression, a metabolic marker present in endothelial tip cells in T2DM mice kidney. 8PN had opposite effects in T2DM mice LV. These XN and 8PN effects were dependent on VEGF levels as revealed by in vitro assays. These findings were accompanied by tissue and plasma reduced expression levels of VEGF-B and its receptors, VEGFR1 and neuropilin-1, by both polyphenols. CONCLUSION:Beer polyphenols modulate T2DM angiogenic paradox in a tissue-dependent manner. We also show for the first time that both polyphenols decreased VEGF-B pathway, which is implicated in endothelial-to-tissue lipid metabolism. Altogether, the effects of these polyphenols in the crosstalk between angiogenesis and metabolism render them potent agents for novel diabetic therapeutic interventions.