Pericyte Pathobiology

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Diabetes

The microvessels of the retina are particularly vulnerable to damage induced by diabetes. An early histological sign of diabetic retinopathy is the loss of pericytes. Currently, the mechanisms causing this sight-threatening complication remain uncertain.

PURINOCEPTORS

Recently, Sugiyama and his colleagues proposed that vasoactive molecules, such as extracellular ATP, can become vasotoxic in the diabetic retina. They found that activation of P2X7 purinoceptors not only plays a role in transducing the contractile response of pericytes to ATP, but also can induce the formation of lethal transmembrane pores. Although high agonist doses are required to open P2X7 pores in nondiabetic retinal microvessels, normally nonlethal concentrations trigger apoptosis in diabetic capillaries. Thus, a diabetes-induced increase in the vulnerability of retinal microvessels to the lethal effect of P2X7 receptor activation may be a previously unrecognized mechanism by which diabetic retinopathy progresses.

Endothelin-1

Because epidemiological studies indicate that hyper-glycemia is a key factor associated with the development of

Vasoconstrictor

I NSC channels

Calcium release-

► pericyte^contraction llunjen jblood flow

Figure 2 Schematic diagram of putative pathways by which vasoactive signals induce pericyte contraction and thereby decrease blood flow. Not shown are possible interactions between calcium release and calcium influx, that is, calcium induced calcium release and store-operated calcium channels. NSC, calcium-permeable nonspecific cation channels; KATP, ATP-sensitive potassium channels; ClCa, calcium-activated chloride channels; VGCC, voltage-gated calcium channels; [Ca2+]j, intracellular calcium concentration.

diabetic retinopathy, the effect of glucose on pericyte responses to vasoactive molecules is of interest. Using cultured bovine pericytes, investigators have found that the contractile response of these cells to endothelin-1 is attenuated when the culture medium contains a high concentration of glucose. Experiments by McGinty and her coworkers indicate that a glycation-induced decrease in the function of L-type VGCC accounts for a reduction in the endothelin-induced influx of calcium and consequently the diminished contractile response of pericytes to this vasoactive molecule. An alteration in the vasoconstrictive effect of endothelin-1 may contribute to the dysfunction of autoregulatory mechanisms observed in the retinal circulation well before the onset of pericyte death and clinical signs of diabetic retinopathy.

Microvascular Gap Junctions

Soon after the onset of experimental diabetes, the intercellular communication system linking pericytes with their neighboring microvascular cells is disrupted by a mechanism involving the upregulation of protein kinase C. This closure of gap junction pathways disrupts the multicellular organization of the retinal microvas-culature and may compromise mechanisms to match local blood flow to the needs of neurons. Not only could the loss of cell-to-cell communication adversely affect neuronal function, but it may metabolically isolate pericytes and contribute to their demise early in the course of diabetic retinopathy.

Blood-Retinal Barrier Breakdown in many retinal disorders, including diabetic retinopathy, the blood-retinal barrier is compromised. At sites where this barrier is defective, serum-derived molecules leak from the blood vessels into the retina. Because pericytes are located on the abluminal surface of the vascular endothelium, they are among the first cells to be exposed to molecules leaking from the circulatory system. As a result, the responses of pericytes to blood-derived molecules may determine how the retina functions when the vascular endothelial barrier is leaky.

in one of the first studies to establish that pericytes are contractile, Kelley and coinvestigators demonstrated that serum causes these cells to contract. More recently, Sakagami and coworkers showed that exposure of isolated pericyte-containing microvessels to serum activates calcium-permeable NSC and ClCa channels. Associated with the opening of these channels, pericytes depolarize, contract, and cause the adjacent lumens to constrict.

Serum-induced contraction of pericytes may be a successful adaptive response to a breakdown of the blood-retinal barrier. For example, contraction of leaky micro-vessels would shunt blood away from areas with a defective vascular endothelium. on the other hand, extensive shunting of blood may cause ischemic damage, contribute to the demise of pericytes, and facilitate the progression of diabetic retinopathy.

Ischemia

Under physiological conditions, PDGF-BB activates NSC and ClCa channels. With the opening of these channels retinal pericytes depolarize and contract (Figure 2). However, during a prolonged inhibition of ATP synthesis, some pericytes hyperpolarize and relax in response to PDGF-BB. This PDGF-induced increase in membrane potential is due to the activation of KATP channels, which close when the intracellular ATP concentration falls to an extremely low level. The capability of a vasoactive signal to elicit vasoconstriction when energy supplies are ample and vasodila-tion under ischemic conditions provides an efficient mechanism to link the function of the microcirculation to the local metabolic needs. Future studies may reveal other dual-action signals that play a role in the regulation of the retinal microcirculation.

Glossary

ATP-sensitive potassium (KATP) channels: Potassium-selective ion channels that are inhibited by intracellular ATP ([ATP]j). By causing a decrease in [ATP]j, ischemia activates these channels, which cause pericytes to hyperpolarize. Although activated as [ATP]i falls from millimolar concentrations, KATP channels require ~10 ||M ATP to remain open. As a result, as [ATP] declines below 10 ||M, these channels again close.

Nonspecific cation (NSC) channels: Ion channels that are permeable to sodium and potassium and, in some cases, calcium. opening these channels causes pericytes to depolarize. Membrane hyperpolarization increases the influx of calcium through calcium-permeable NSC channels.

P2X7 purinoceptors: A member of the family of receptor-operated channels activated by extracellular ATP Unlike nearly all other types of ion channels, the sustained activation of P2X7 purinoceptors is associated with the formation of transmembrane pores, which can cause cell death.

Pericytes: Cells located on the outer walls of capillaries and postcap-illary venules. Thought to play a role in regulating blood flow, maintaining vessel structure, and inhibiting endothelial proliferation. The loss of these cells is an early histological sign of diabetic retinopathy.

Voltage-gated calcium channels: ion channels that are selectively permeable to calcium and activated by membrane depolarization.

Further Reading

Kawamura, H., Sugiyama, T., Wu, D. M., Kobayashi, M., Yamanishi, S., Katsumura, K., and Puro, D. G. (2003). ATP: A vasoactive signal in the pericyte-containing microvasculature of the rat retina. J. Physiol. 551, 787-799. The online version of this paper, which is at DOI: 10.1113/jphysiol.2003.047977, contains a link to a time-lapse movie showing induced contractions of a pericyte-containing microvessel.

Kelley, C., D'Amore, P., Hechtman, H. B., and Shepro, D. (1987). Microvascular pericyte contractility in vitro: Comparison with other cells of the vascular wall. J. Cell Biol. 104, 483-490. An early paper using a silicone substrate to detect cellular contraction in cultures of retinal pericytes.

McGinty, A., Scholfield, C. N., Liu, W. H., Anderson, P., Hoey, D. E., and Trimble, E. R. (1999). Effect of glucose on endothelin-1-induced calcium transients in cultured bovine retinal pericytes. J. Biol. Chem. 274, 25250-25253.

Oku, H., Kodama, T., Sakagami, K., and Puro, D. G. (2001). Diabetes-induced disruption of gap junction pathways within the retinal microvasculature. Invest. Ophthalmol. Vis. Sci. 42, 1915-1920.

Rhinehart, K., Zhang, Z., and Pallone, T. L. (2002). Ca2+ signaling and membrane potential in descending vasa recta pericytes and endothelia. Ami. J. Physiol. Renal Physiol. 283, F852-F860. Although pericytes of the retina have received the most attention, there is a substantial literature on pericytes from other vascular beds. In this paper, the authors studied pericytes of the kidney.

Sugiyama, T., Kobayashi, M., Kawamura, H., Li, Q., and Puro, D. G. (2004). Enhancement of P2X7-induced pore formation and apoptosis: an early effect of diabetes on the retina microvasculature. Invest. Ophthalmol. Vis. Sci. 45, 1026-1032.

Capsule Biography

Dr. Puro is professor of Ophthalmology and Visual Science and of Molecular and Integrative Physiology at the University of Michigan. He was named in 2001 as the recipient of the Harrington RBP Senior Scientist Award. His research focuses on the physiology and pathobiology of retinal capillaries; his laboratory is supported by grants from the NIH, the American Diabetes Association, and Research to Prevent Blindness, Inc.

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