Glucose-6-phosphate Dehydrogenase Modulates Vascular Endothelial Growth Factor-mediated Angiogenesis

Abstract

Glucose-6-phosphate dehydrogenase (G6PD), the first enzyme of the pentose phosphate pathway, is the principal intracellular source of NADPH. NADPH is utilized as a cofactor by vascular endothelial cell nitric-oxide synthase (eNOS) to generate nitric oxide (NO ⅐ ). To determine whether G6PD modulates NO ⅐ -mediated angiogenesis, we decreased G6PD expression in bovine aortic endothelial cells using an antisense oligodeoxynucleotide to G6PD or increased G6PD expression by adenoviral gene transfer, and we examined vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation, migration, and capillary-like tube formation. Deficient G6PD activity was associated with a significant decrease in endothelial cell proliferation, migration, and tube formation, whereas increased G6PD activity promoted these processes. VEGF-stimulated eNOS activity and NO ⅐ production were decreased significantly in endothelial cells with deficient G6PD activity and enhanced in G6PD-overexpressing cells. In addition, G6PD-deficient cells demonstrated decreased tyrosine phosphorylation of the VEGF receptor Flk-1/ KDR, Akt, and eNOS compared with cells with normal G6PD activity, whereas overexpression of G6PD enhanced phosphorylation of Flk-1/KDR, Akt, and eNOS. In the Pretsch mouse, a murine model of G6PD deficiency, vessel outgrowth from thoracic aorta segments was impaired compared with C3H wild-type mice. In an in vivo Matrigel angiogenesis assay, cell migration into the plugs was inhibited significantly in G6PD-deficient mice compared with wild-type mice, and gene transfer of G6PD restored the wild-type phenotype in G6PD-deficient mice. These findings demonstrate that G6PD modulates angiogenesis and may represent a novel angiogenic regulator.

Glucose-6-Phosphate Dehydrogenase Deficiency Improves Insulin Resistance With Reduced Adipose Tissue Inflammation in Obesity

“…Meanwhile, G6PD mut mice developed through ENU random mutagenesis with C3H mice are viable and display no apparent chronic hemolysis despite low G6PD activity (27). To date, G6PD mut mice have been studied for various pathological conditions such as sepsis, teratogenesis, cardiovascular diseases, myocardial dysfunction, and atherosclerosis (17,18,(20)(21)(22)(30)(31)(32)42,43). Because of their genetic background, C3H G6PD mut mice have some limitations for investigating obesity-mediated chronic inflammation and metabolic dysregulation.…”

Increased prevalence of proliferative retinopathy in patients with type 1 diabetes who are deficient in glucose-6-phosphate dehydrogenase

“…The decreased supply of NADPH, by limiting the regeneration of reduced glutathione, may magnify any level of oxidant stress occurring in diabetes. Additionally, if the observations made in cultured endothelial cells and in animals [3] apply to human G6PD deficiency, the decreased NADPH supply could affect eNOS activity, and thus reduce NO availability and endothelial performance. Of note, a facet of the impaired endothelial performance in in vitro and in vivo models of G6PD deficiency is an attenuated response to vascular endothelial growth factor and decreased angiogenesis [3].…”

“…Additionally, if the observations made in cultured endothelial cells and in animals [3] apply to human G6PD deficiency, the decreased NADPH supply could affect eNOS activity, and thus reduce NO availability and endothelial performance. Of note, a facet of the impaired endothelial performance in in vitro and in vivo models of G6PD deficiency is an attenuated response to vascular endothelial growth factor and decreased angiogenesis [3]. Our diabetic patients with G6PD deficiency showed that the endothelial cells of retinal vessels respond to angiogenic cues and form new vessels.…”

“…The main clinical manifestation of G6PD deficiency is a haemolytic anaemia, occurring because the erythrocytes, which rely exclusively on the pentose phosphate pathway to generate NADPH, are insufficiently protected from oxidation in the presence of drugs, infections and consumption of broad beans (or fava beans, 'favism') [2]. G6PD deficiency could also contribute to diabetic vascular disease by magnifying endothelial dysfunction, as NADPH is a required cofactor for endothelial nitric oxide synthase (eNOS) [3]. On the other hand, the reduced cellular supply of NADPH could protect from mechanisms of diabetic tissue damage.…”

The Novel SPARC Family Member SMOC-2 Potentiates Angiogenic Growth Factor Activity

“…In Vitro Cell-network Formation Assay-The formation of network-like structures by HUVECs on Matrigel (BD Biosciences) was performed as previously described (31). The 12-well culture plates were coated with Matrigel according to the manufacturer's instructions.…”