Vasodilation of rat retinal microvessels induced by monobutyrin. Dysregulation in diabetes.

Abstract

1-Butyryl-glycerol (monobutyrin) is a simple lipid product of adipocytes with angiogenic activity. Recent studies have shown that the biosynthesis ofthis compound is tightly linked to lipolysis, a process associated with changes in blood flow. We now present data indicating that monobutyrin is an effective vasodilator of rodent blood vessels using a fluorescent retinal angiogram assay. The vasodilatory activity of monobutyrin is potent (ED50 = 3.3 X 10-7 M), dose dependent, and stereospecific.Because diabetes represents a catabolic, lipolytic state with numerous vascular complications, we examined the action and regulation of monobutyrin in insulin-deficient diabetic rats. Serum levels of monobutyrin in streptozotocin-induced diabetic rats were greatly elevated compared to normal animals. At the same time, the retinal vessels of the diabetic animals develop a resistance to the vasodilatory activity of monobutyrin. These results demonstrate a role for monobutyrin in the control of vascular tone and suggest a possible involvement in the pathology of diabetes. (J. Clin. Invest. 1993. 92:2872-2876

Pioglitazone enhances collateral blood flow in ischemic hindlimb of diabetic mice through an Akt-dependent VEGF-mediated mechanism, regardless of PPARγ stimulation

“…Diabetes-induced impairment of collateral formation has been also demonstrated in murine models: hindlimb ischemia created by ligation of the femoral artery is associated with a reduced formation of capillaries and a reduction in blood flow to the ischemic limb in diabetic versus non-diabetic mice [ 44 ]. Thus, several agents are implicated in development of abnormal angiogenesis in diabetes mellitus, including dysregulation of VEGF local expression [ 45 , 46 ] and other growth factors or cytokines imbalances [ 47 , 48 ] in a general metabolic derangement [ 49 ].…”

Retinal Blood Flow in Diabetes

“…The sum of the squares of the retinal artery and vein diameters divided by the mean circulation time is proportional to the retinal blood flow under the assumption that the retina is fully perfused (the sum of the squares of the retinal artery and vein diameters is proportional to the perfused vascular volume). The methodology for these measurements has been described in detail [13] and the measurements have been validated using vasoactive agents that produce known vasoconstrictory and vasodilatory changes [14, 15].…”

Abnormal angiogenesis in diabetes mellitus

“…118 Initially purified from adipocyte-conditioned media based on its ability to induce neovascularization in the chick chorioallantoic membrane assay, monobutyryn was shown to induce an immediate, dosedependent increase in retinal blood-flow rate. 118 However, in the longer term, diabetic rat retinal blood vessels developed resistance to vasodilatation by monobutyrin, suggesting the involvement of a negative feedback loop by which the excess monobutyrin downregulates or desensitizes the specific receptor or protein which mediates its effect. 118 The resulting decrease in retinal flow leads to regions of low-or non-perfusion, and subsequent ischemia may trigger the release of various proangiogenic growth factors.…”

“…118 However, in the longer term, diabetic rat retinal blood vessels developed resistance to vasodilatation by monobutyrin, suggesting the involvement of a negative feedback loop by which the excess monobutyrin downregulates or desensitizes the specific receptor or protein which mediates its effect. 118 The resulting decrease in retinal flow leads to regions of low-or non-perfusion, and subsequent ischemia may trigger the release of various proangiogenic growth factors.…”