Abstract 18610: Mitochondrial Transfer Restores Endothelial Dependent Vasodilation

Abstract

Although endothelial dysfunction is a hallmark of vascular disease, the mechanisms underlying this impairment are unknown. Recently, impaired mitochondrial function was observed in vascular pathologies with endothelial dysfunction; yet a causal link between mitochondrial and endothelial function is not established. We sought to establish this link by demonstrating that restoration of mitochondrial function rescues endothelium-dependent dilation in a model of endothelial dysfunction (metabolic syndrome). Initially, we evaluated activities of mitochondrial complexes I-IV in aortas), and endothelial-dependent dilation (isolated, perfused mesenteric small arteries [MA’s], 289±32 µm, id) in Zucker Obese Fatty (ZOF) and Zucker Lean (LN) rats. Activity of complex I, II, III, or IV (per mg/mitochondrial protein) was lower (56%, 65%, 72% or 59% reduction, respectively) in ZOF than LN (P<0.05). Dilation to the endothelium-independent agonist, nitroprusside (NP) was equivalent in LN and ZOF rats suggesting normal smooth muscle function. Dilation to vasoactive intestinal peptide (VIP, endothelium-dependent agonist) in LN was completely blocked by L-NAME (10 -4 M) (Figure 1). Dilation to VIP was markedly compromised in ZOF (Figure 1). To acutely restore mitochondrial function, mitochondria from livers of lean rats were isolated, labeled with Mitotracker, administered into the perfusion circuit, and “transferred” into the endothelium of MA’s of ZOF via electroporation (confirmed by Mitotracker fluorescence). Thirty minutes after electroporation, dilation of mitochondria-treated vessels (ZOF+Mito) was restored to near normal levels (Figure 1, ZOF+Mito vs LN) and significantly greater than untreated ZOF. Dilation to NP was unaffected by transfer (not shown). These results suggest that mitochondria play a key role in endothelial function, and that treatment regimens for vascular disease should consider mitochondrial directed therapies.