Donald G Puro

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University of Michigan

Although constituting the largest portion of the circulatory system and the sites of greatest resistance, capillaries traditionally have been thought to play only a passive role in the regulation of blood flow. However, evidence is accumulating that blood flow can be actively controlled at the capillary level in at least in some vascular beds. Experimental support for the concept that capillaries actively regulate local perfusion is based chiefly on studies of the retinal vasculature.

Role of Pericytes in Blood Flow Regulation

The microcirculation of the retina is anatomically and physiologically specialized to distribute oxygen and nutrients to areas of metabolic need within a tissue that must be translucent.

Specialized Features of the Retinal Vasculature

One adaptation that minimizes interference with light passing through the retina is the low density of capillaries. In the retina, the intercapillary distance is at least 50 mm, which is less dense than in other tissues. Although the relatively paucity of retinal capillaries is a successful compromise between visual function and nutritive needs, a consequence is that there little functional reserve. As a result, a tight link between local perfusion and neuronal metabolism is essential in the retina.

Having blood flow controlled exclusively by local conditions facilitates efficiency in the distribution of oxygen and nutrients within the retina. Local control is ensured by the absence of autonomic innervation, which limits extrinsic oversight by the central nervous system. Also, the presence of an endothelial barrier restricts the effects of circulating vasoactive molecules. In addition, the lack of precapillary smooth muscle sphincters, which control local perfusion in most other tissues, suggests that retinal blood may be regulated within capillaries, rather than exclusively at precapil-lary sites.

Pericytes as Regulators of Capillary Perfusion

Candidates for regulating retinal blood flow at the capillary level are the pericytes. As in nearly all vascular beds, these abluminally located cells envelop the capillaries and postcapillary venules of the retina. Suggestive of the particular importance of pericytes in the retinal microcirculation, the density of these cells is greatest in the retina. Their expression of molecules such as a-smooth muscle actin supports the hypothesis that pericytes are contractile elements of the microvasculature. By contracting or relaxing, pericytes may adjust lumen size and thereby control capillary perfusion. However, even though vasoconstriction is observed in isolated retinal microvessels at sites adjacent to contracting pericytes, it remains to be definitively demonstrated that these cells regulate capillary blood flow in vivo.

Regulation of Pericyte Contractility

Assay Systems

Knowledge of the regulation of pericyte contractility is based on several experimental assay systems.

Cultured Retinal Pericytes

Many studies testing the effects of vasoactive molecules use cells grown on a silicone surface. The laboratories of

D'Amore and Shepro pioneered in developing this assay system for retinal pericytes. Contraction of these cells is detected by the induction of wrinkles in the underlying silicone. An advantage of using a culture system is that only pericytes are present. Thus, indirect effects mediated by other types of cells are excluded. However, one disadvantage is that pericytes are likely to change during long-term culture. Certainly the exquisite morphology of in vivo pericytes is lost, as the cells quickly become rather nondescript flat cells in vitro; molecular and physiological changes may also occur. Furthermore, the tens of minutes that are often required for the induction of wrinkles in the silicone preclude assessment of pericyte responses within shorter time periods that may be more physiologically relevant.

Isolated Retinal Microvessels

More recently, Puro and his associates have used differential interference optics and time-lapse photography to detect pericyte contraction and relaxation in microvessels freshly isolated from the rat retina. Pericytes in the isolated microvessels retain their morphology and maintain a close association with the underlying endothelial tube. Because retinal pericytes are coupled via gap junctions to dozens of neighboring vascular cells, the ability to study pericytes that are an integral component of a multicellular functional unit can reveal a more complete picture of how the retinal microvasculature responds to vasoactive signals. Another advantage is the ability to detect pericyte contraction or relaxation, as well as microvascular constriction or dilation, within seconds after the onset of exposure to vasoactive substances. However, a caution is that findings based on studies of isolated microvascular complexes must ultimately be confirmed in vivo.

Retinal Capillaries in Situ

Funk and his colleagues have shown that it is feasible to monitor the effects of various vasoactive chemicals on the diameters of capillaries in isolated rat retinas. This in situ assay system should be useful, although a direct assessment of pericyte contraction or relaxation in situ has yet to be reported. A deficiency in both the in situ system and the use of isolated microvessels is that the vascular lumens are not perfused during an experiment. As a result, the role of shear stress and other intraluminal forces in determining the microvascular response to vasoactive molecules cannot be assessed. A challenging goal is to visualize in vivo the changes in pericyte shape, lumen diameter, and blood flow induced by vasoactive signals.

Contractile Responses to Vasoactive Molecules

Putative vasoactive molecules, which are known to affect the contractile tone of retinal pericytes, originate from a number of sources (Figure 1). Sites include the underlying endothelial cells that form the capillary tube, the glia that ensheathe the pericyte/endothelial complex, and the neurons that release vasoactive neurotransmitters. In addition, a

Metabolic conditions carbon dioxide acidic pH adenosine _oxygen_

Glia

Pericyte

Neurons acetylcholine dopamine norepinephrine serotonin

Endothelial cells nitric oxide endothelin-1 angiotensin II

PDGF-BB prostaglandin I. bradykinin

Vascular system atrial naturetic peptide thrombin thromboxane Aj histamine

Italics = induces pericyte relaxation Bold = induces pericyte contraction

Figure 1 Schematic diagram of the likely sources of the vasoactive signals that are known to regulate the contractility of retinal pericytes. PDGF-BB, platelet-derived growth factor-BB.

breakdown of the blood-retinal barrier exposes pericytes to molecules from the vascular system.

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