thymosin-beta(4) and Diabetic-Angiopathies

Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors.. This study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus.. Diabetic human myocardial explants revealed capillary rarefaction and pericyte loss compared to nondiabetic explants. Hyperglycemia in db pigs, even without ischemia, induced capillary rarefaction in the myocardium (163 ± 14 c/hpf in db vs. 234 ± 8 c/hpf in wt hearts; p < 0.005), concomitant with a distinct loss of EF (44.9% vs. 53.4% in nondiabetic controls; p < 0.05). Capillary density further decreased in chronic ischemic hearts, as did EF (both p < 0.05). Treatment with rAAV.Tβ4 enhanced capillary density and maturation in db hearts less efficiently than in wt hearts, similar to collateral growth. rAAV.VEGF-A, though stimulating angiogenesis, induced neither pericyte recruitment nor collateral growth. As a result, rAAV.Tβ4 but not rAAV.VEGF-A improved EF in db hearts (34.5 ± 1.4%), but less so than in wt hearts (44.8 ± 1.5%).. Diabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV.Tβ4 in a translational large animal model of hibernating myocardium.

Topics: Animals; Coronary Disease; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Genetic Therapy; Heart Failure; Heart Transplantation; Humans; Microvessels; Myocardial Stunning; Myocardium; Neovascularization, Physiologic; Stroke Volume; Swine; Thymosin; Translational Research, Biomedical; Vascular Endothelial Growth Factor A