DIABETES MELLITUS AND VASCULAR DISEASE: POSSIBLE ROLE OF HYDROXYACIDS IN ITS GENESIS

Studies to date have not elucidated the cause(s) for diabetic neovascular proliferation. We report that a metabolite of arachidonic acid (AA), 15 hydroxyeicosatetraenoic acid (15HETE) is present in vessels, plays a role in neovascularization, and is ↑in infants of diabetic mothers (IDM). When human umbilical arterial microsomes were incubated with 14C AA, besides the cyclooxygenase products, three hydroxyacids were observed. Two of the HPLC purified metabolites were confirmed by G.C-MS to be 11HETE and 15HETE We next evaluated the production of these hydroxyacids in umbilical arteries from 12 control neonates and 16 IDM. Incubation of 1 mg total membrane protein with 14C AA for 10' generated 322±152 (1SD) pmol total HETES and 81±24 pmol 15HETE in controls. Total HETE production in the IDM was ↑ to 478±190 (p<0.05), while the ↑ in production of 15HETE was of even greater magnitude (122±40;p < 0.005). Finally, we evaluated the effect of 15HETE on a crucial aspect of angiogenesis i.e. endothelial cell migration using a modified Boyden chamber (Nature 288:483). Upper wells contained fetal bovine aortic endothelium in MEM-10, while lower wells contained the potential migration modulators. Control MEM 10 or AA caused no migration. Bovine retinal extract, a known potent migration stimulator, ↑ migration by 269±10%. 15HETE ↑ migration by 115±28%. Previous studies in the IDM have shown that neonatal platelet AA metabolism at birth accurately reflects maternal platelet function. Our study, using vascular tissue obtained from the diabetic milieu, demonstrates a potential role for 15HETE in the pathogenesis of diabetic neovascular proliferative disease.