Extracellular lactate as a dynamic vasoactive signal in the rat retinal microvasculature

Abstract

We tested the hypothesis that extracellular lactate regulates the function of pericyte-containing retinal microvessels. Although abluminally positioned pericytes appear to adjust capillary perfusion by contracting and relaxing, knowledge of the molecular signals that regulate the contractility of these mural cells is limited. Here, we focused on lactate because this metabolic product is in the retinal extracellular space under both physiological and pathophysiological conditions. In microvessels freshly isolated from the adult rat retina, we used perforated-patch pipettes to monitor ionic currents, fura-2 to measure calcium levels, and time-lapse photography to visualize changes in mural cell contractility and lumen diameter. During lactate exposure, pericyte calcium rose; these cells contracted, and lumens constricted. This contractile response appears to involve a cascade of events resulting in the inhibition of Na+/Ca2+ exchangers (NCXs), the decreased of which function causes pericyte calcium to increase and contraction to be triggered. On the basis of our observation that gap junction uncouplers minimized the lactate-induced rise in pericyte calcium, we propose that the NCXs inhibited by lactate are predominately located in the endothelium. Indicative of the importance of endothelial/pericyte gap junctions, uncouplers of these junctions switched the pericyte response to lactate from contraction to relaxation. In addition, we observed that hypoxia, which closes microvascular gap junctions, also switched lactate's effect from vasocontraction to vasorelaxation. Thus the response of pericyte-containing retinal microvessels to extracellular lactate is metabolically modulated. The ability of lactate to serve as a vasoconstrictor when energy supplies are ample and a vasodilator under hypoxic conditions may be an efficient mechanism to link capillary function with local metabolic need.

Bioelectric impact of pathological angiogenesis on vascular function

“…5). Also similar to hypoxia and consistent with lactate's role as a vasodilator in the normal retinas (15,(19)(20)(21), arterioles within both control and >P40 ROP retinas-whose vessels were not suprahyperpolarized (Fig. 1C)-dilated in response to lactate (Fig.…”

“…Based on our earlier study of retinovessels (20), we considered a role for a cascade of events involving lactate, MCT, and NCX. Previously, we found that under certain conditions, the activation of this cascade can cause retinovessels to contract (20), although this vasoconstricting influence is usually vitiated by the potent vasorelaxing impact of lactate on precapillary arterioles (21), as well as on larger retinal arterioles, in which the activation of a voltage-changing K ATP current plays a key role (15). However, we posited that the relative impact of the lactate/MCT/NCX pathway would be boosted when suprahyperpolarization to a voltage near E K , as observed in <P30 ROP retinas (Fig.…”

Brain Lactate Metabolism: The Discoveries and the Controversies

“…Several studies have reported that lactate increases vasodilation by different mechanisms (Hein et al, 2006;Yamanishi et al, 2006;Gordon et al, 2008), and continuous lactate release from the activated brain may serve a signaling function to increase blood flow and fuel delivery to the brain. As glucose delivery to the brain exceeds demand for glucose over a wide range of CMR glc (Cremer et al, 1983;Hargreaves et al, 1986), lactate release and its use as a blood flow regulator need not be a 'waste' of fuel, because lactate can be used by peripheral tissues as fuel or as a gluconeogenic substrate.…”

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…The sites of pericyte/endothelial interactions are altered in pathological disease. In diabetes and cerebral oedema, gap junctions are substantially decreased in the retina and disrupted in retinal pericytes (Yamanishi et al, 2006), indicating the importance of pericyte-endothelial cell communication for adaptability to injury.…”