Functional, Cellular, and Molecular Characterization of the Angiogenic Response to Chronic Myocardial Ischemia in Diabetes

Abstract

Background-Ischemic heart disease is the most common cause of mortality in diabetic patients. Although therapeutic angiogenesis is an attractive option for these patients, they appear to have reduced collateral formation in response to myocardial ischemia. The aims of this study were to establish a large animal model of diabetes and chronic myocardial ischemia, evaluate the effects of diabetes on the angiogenic response, and elucidate the molecular pathways involved. Methods and Results-Diabetes was induced in male Yucatan miniswine using a pancreatic ␤-cell specific toxin, alloxan (150 mg/kg; nϭ8). Age-matched swine served as controls (nϭ8). Eight weeks after induction, chronic ischemia was induced by ameroid constrictor placement around the circumflex coronary artery. Myocardial perfusion and function were assessed at 3 and 7 weeks after ameroid placement using isotope-labeled microspheres. Endothelial cell density and myocardial expression of angiogenic mediators was evaluated. Diabetic animals exhibited significant endothelial dysfunction. Collateral dependent perfusion and LV function were significantly impaired in diabetic animals. Diabetic animals also demonstrated reduced endothelial cell density (173Ϯ14 versus 234Ϯ23 cells/hpf, Pϭ0.03). Expression of VEGF, Ang-1, and Tie-2 was reduced, whereas antiangiogenic proteins, angiostatin (4.4Ϯ0.9-fold increase, PϽ0.001), and endostatin (2.9Ϯ0.4-fold increase, Pϭ0.03) were significantly elevated in the diabetic myocardium. Conclusions-Diabetes

Inflammatory stress in primary venous and aortic endothelial cells of type 1 diabetic mice

“…Such findings suggest that vascular repair mechanisms are blunted. Indeed, one of the test genes in the array, VEGFa, a prototypical mediator of vascular survival, 26 was not impacted by the diabetic state.…”

“…For example, Thbs1 (a negative regulator of angiogenesis), 26 was increased in diabetic aortic ECs in short-term diabetes and in both aortic and venous ECs in long-term diabetes. Such findings suggest that vascular repair mechanisms are blunted.…”

Role of angiostatins in diabetic complications

“…В работе [122] было установлено, что в биопсийном материале миокарда пациентов с диабетом II типа уровень VEGF превышал норму, однако при этом наблюдались снижение активности его рецептора и аберрации сигнальных путей. В противоположность этим результатам, в другом исследовании было обнаружено падение уровня VEGF у карликовых свиней с экспериментальным диабетом в ответ на хроническую ишемию [123]. Данные различия могут быть обусловлены видовыми особенностями протекания патологического процесса, хотя нельзя исключить и влияние препаратов, применявшихся для лечения больных диабетом.…”

“…Позже, на целом ряде адекватных экспериментальных моделей были получены сходные результаты. Было обнаружено почти 4-кратное увеличение содержания AS в ткани миокарда в условиях хронической диабет-ассоциированной ишемии [123]. Таким образом, разработка подходов, направленных на регуляцию локального уровня AS, позволит открыть широкие перспективы для высокоэффективной терапии таких фатальных диабетических осложнений, как ССЗ.…”

Limb Salvage in Diabetic Patients: The Italian Experience

“…Usually a large part of diabetic patients affected by CLI are elderly with several comorbidity. Therefore they can't tolerate a surgical procedure for the high operative risk and secondly it is often no possible to pack a by-pass because of the absence of a suitable vein and due to the presence of a local infection that may not guarantee an adequate anastomosis site [43,45,46,[52][53][54][55].…”