Kawamura, H. et al. Effects of angiotensin II on the pericyte-containing microvasculature of the rat retina. J. Physiol. (Lond.) 561, 671-683

Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105, USA.
The Journal of Physiology (Impact Factor: 5.04). 01/2005; 561(Pt 3):671-83. DOI: 10.1113/jphysiol.2004.073098
Source: PubMed


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.

Full-text preview

Available from:
  • Source
    • "The way in during which central innervation and local vasoactive signals regulate pericyte tone in vivo, however, remains poorly understood. Studies of retinal capillaries suggest that pericytes react to intrinsic signaling in much the same way as smooth muscle cells: Pericyte constrictions have hence been observed in response to mechanical stretch and exposure to angiotensin II (via AT1 receptors) [55] and endothelin-1 (via ETA receptors) [91], by a Ca++ dependent mechanism [25]. Meanwhile, pericytes relax in response to adenosine [68], ATP [56], and nitric oxide (NO) [37, 38], as well as to cholinergic [117] and adrenergic (via β2 receptors) [25] stimulation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ischemic heart disease (IHD) is characterized by an imbalance between oxygen supply and demand, most frequently caused by coronary artery disease (CAD) that reduces myocardial perfusion. In some patients, IHD is ascribed to microvascular dysfunction (MVD): microcirculatory disturbances that reduce myocardial perfusion at the level of myocardial pre-arterioles and arterioles. In a minority of cases, chest pain and reductions in myocardial flow reserve may even occur in patients without any other demonstrable systemic or cardiac disease. In this topical review, we address whether these findings might be caused by impaired myocardial oxygen extraction, caused by capillary flow disturbances further downstream. Myocardial blood flow (MBF) increases approximately linearly with oxygen utilization, but efficient oxygen extraction at high MBF values is known to depend on the parallel reduction of capillary transit time heterogeneity (CTH). Consequently, changes in capillary wall morphology or blood viscosity may impair myocardial oxygen extraction by preventing capillary flow homogenization. Indeed, a recent re-analysis of oxygen transport in tissue shows that elevated CTH can reduce tissue oxygenation by causing a functional shunt of oxygenated blood through the tissue. We review the combined effects of MBF, CTH, and tissue oxygen tension on myocardial oxygen supply. We show that as CTH increases, normal vasodilator responses must be attenuated in order to reduce the degree of functional shunting and improve blood-tissue oxygen concentration gradients to allow sufficient myocardial oxygenation. Theoretically, CTH can reach levels such that increased metabolic demands cannot be met, resulting in tissue hypoxia and angina in the absence of flow-limiting CAD or MVD. We discuss these predictions in the context of MVD, myocardial infarction, and reperfusion injury.
    Full-text · Article · May 2014 · Archiv für Kreislaufforschung
  • Source
    • "First, CTTH might, in theory, be reduced by reversing capillary constrictions caused by pericytes. Pericytes have been reported to constrict in response to stimulation of b 2 -adrenergic receptors (Zschauer et al., 1996), AT 1 angiotensin II receptors (Kawamura et al., 2004; Matsugi et al., 1997), and endothelin-1 receptors (Dehouck et al., 1997) via a calcium channel-dependent mechanism in vitro. Blockage of specific receptor systems that can cause widespread pericyte constriction would therefore be expected to reduce CTTH and upstream neurovascular dysfunction. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dogs with Canine Cognitive Dysfunction (CCD) accumulate amyloid beta (Aβ) in the brain. As the cognitive decline and neuropathology of these old dogs share features with Alzheimer's disease (AD), the relation between Aβ and cognitive decline in animal models of cognitive decline is of interest to the understanding of AD. However, the sensitivity of the biomarker Pittsburgh Compound B (PiB) to the presence of Aβ in humans and in other mammalian species is in doubt. To test the sensitivity and assess the distribution of Aβ in dog brain, we mapped the brains of dogs with signs of CCD (n = 16) and a control group (n = 4) of healthy dogs with radioactively labeled PiB ([(11)C]PiB). Structural magnetic resonance imaging brain scans were obtained from each dog. Tracer washout analysis yielded parametric maps of PiB retention in brain. In the CCD group, dogs had significant retention of [(11)C]PiB in the cerebellum, compared to the cerebral cortex. Retention in the cerebellum is at variance with evidence from brains of humans with AD. To confirm the lack of sensitivity, we stained two dog brains with the immunohistochemical marker 6E10, which is sensitive to the presence of both Aβ and Aβ precursor protein (AβPP). The 6E10 stain revealed intracellular material positive for Aβ or AβPP, or both, in Purkinje cells. The brains of the two groups of dogs did not have significantly different patterns of [(11)C]PiB binding, suggesting that the material detected with 6E10 is AβPP rather than Aβ. As the comparison with the histological images revealed no correlation between the [(11)C]PiB and Aβ and AβPP deposits in post-mortem brain, the marked intracellular staining implies intracellular involvement of amyloid processing in the dog brain. We conclude that PET maps of [(11)C]PiB retention in brain of dogs with CCD fundamentally differ from the images obtained in most humans with AD.
    Full-text · Article · Dec 2013 · Frontiers in Aging Neuroscience
  • Source
    • "The presence of pericytes along microvessels and their contractile capabilities was 'however' revealed in the late 19th and early 20th centuries (Rouget 1879, Krogh 1929), although this was largely overlooked until more recently (Pallone 1994, Pallone & Silldorff 2001, Pallone & Mattson 2002, Kawamura et al. 2004, Peppiatt et al. 2006, Puro 2007, Crawford et al. 2011, 2012). Pericytes are singular smooth muscle-like cells residing on the abluminal side of the endothelium. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Regulation of medullary blood flow (MBF) is essential in maintaining normal kidney function. Blood flow to the medulla is supplied by the descending vasa recta (DVR), which arise from the efferent arterioles of juxtamedullary glomeruli. DVR are composed of a continuous endothelium, intercalated with smooth muscle-like cells called pericytes. Pericytes have been shown to alter the diameter of isolated and in situ DVR in response to vasoactive stimuli that are transmitted via a network of autocrine and paracrine signalling pathways. Vasoactive stimuli can be released by neighbouring tubular epithelial, endothelial, red blood cells and neuronal cells in response to changes in NaCl transport and oxygen tension. The experimentally described sensitivity of pericytes to these stimuli strongly suggests their leading role in the phenomenon of MBF autoregulation. Because the debate on autoregulation of MBF fervently continues, we discuss the evidence favouring a physiological role for pericytes in the regulation of MBF and describe their potential role in tubulo-vascular cross-talk in this region of the kidney. Our review also considers current methods used to explore pericyte activity and function in the renal medulla.
    Full-text · Article · Nov 2012 · Acta Physiologica
Show more