Effects of angiotensin II on the pericyte‐containing microvasculature of the rat retina

Abstract

The aim of this study was to identify the mechanisms by which angiotensin II alters the physiology of the pericyte-containing microvasculature of the retina. Despite evidence that this vasoactive signal regulates capillary perfusion by inducing abluminal pericytes to contract and thereby microvascular lumens to constrict, little is known about the events linking angiotensin exposure with pericyte contraction. Here, using microvessels freshly isolated from the adult rat retina, we monitored pericyte currents via perforated-patch pipettes, measured pericyte calcium levels with fura-2 and visualized pericyte contractions and lumen constrictions by time-lapse photography. We found that angiotensin activates nonspecific cation (NSC) and calcium-activated chloride channels; the opening of these channels induces a depolarization that is sufficient to activate the voltage-dependent calcium channels (VDCCs) expressed in the retinal microvasculature. Associated with these changes in ion channel activity, intracellular calcium levels rise, pericytes contract and microvascular lumens narrow. Our experiments revealed that an influx of calcium through the NSC channels is an essential step linking the activation of AT 1 angiotensin receptors with pericyte contraction. Although not required in order for angiotensin to induce pericytes to contract, calcium entry via VDCCs serves to enhance the contractile response of these cells. In addition to activating nonspecific cation, calcium-activated chloride and voltage-dependent calcium channels, angiotensin II also causes the functional uncoupling of pericytes from their microvascular neighbours. This inhibition of gap junction-mediated intercellular communication suggests a previously unappreciated complexity in the spatiotemporal dynamics of the microvascular response to angiotensin II.

Descending vasa recta endothelium is an electrical syncytium

“…Similarly, connexins are regulated by many factors such as phosphorylation events, pH, and elevation of [Ca 2ϩ ] cyt (8,15,19,24,52). Stimulation by agonists such as endothelin and angiotensin II affects opening of gap junctions so that residual effects of those and other hormones occurring in vivo may be responsible for setting the relative open state of myoendothelial junctions (30,31).…”

Diabetes-Induced Inhibition of Voltage-Dependent Calcium Channels in the Retinal Microvasculature: Role of Spermine

“…3,4,17,20,28,29 However, we have reported that VDCCs have only a modulatory role. 21 Rather, vasoactive signals induce localized capillary constrictions or dilations by way of VDCCindependent mechanisms involving the activation of calciumpermeable, nonspecific cation channels, the release of calcium stores, or the action of the sodium/calcium exchanger. 17,19,21 However, because of efficient gap junction-mediated transmission in the retinal microvasculature, 6 a voltage change generated in the capillary network can result in a voltage-driven vasomotor responses in the VDCC-rich feeder vessel.…”

Pericyte Loss in Diabetic Retinopathy: Mechanisms and Consequences

“…In the eye, RAS contributes to the diabetes-induced damage through two different mechanisms: the over-activation of AT 1 R by high levels of angiotensin II increases VEGF expression in pericytes, leading to vascular leakage [82], pericyte-mediated vasoconstriction [83], oxidative stress [84], thickening of the basement membrane [85] and NF-κB activation [86]. Moreover, RAS has been described to play a role in several of the biochemical dysfunctions described in the following paragraph, which are directly induced by hyperglycaemia: angiotensin II increases AGE formation [87], protein kinase C (PKC) synthesis [88] and ROS production [82], and enhances the flux through the polyol pathway [89], while hyperglycaemia induces angiotensinogen gene expression through the hexosamine pathway [90].…”