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PubMed1993

Regulation of fibronectin and laminin synthesis by retinal capillary endothelial cells and pericytes in vitro.

Retinal capillaries are composed of endothelial cells resting on a basement membrane, in which are embedded pericytes. In diabetes mellitus, the basement membrane becomes thickened, and there is a loss of pericytes. The relative contributions of endothelial cells and pericytes to the synthesis of extracellular matrix proteins which are components of the basement membrane are not well-characterized. To determine how a selective loss of pericytes might affect the composition of retinal capillary basement membranes, we used primary cultures of bovine retinal capillary endothelial cells and pericytes to determine the forms and quantify the amounts of laminin and fibronectin synthesized and secreted by these cell types as well as to determine how high glucose concentrations alter these parameters. Results of ELISAs showed that pericyte cell/matrix layers contained nearly ten times more fibronectin than endothelial cells (288 +/- 24 vs. 34 +/- 5 ng micrograms-1 DNA, P < 0.001), but the amounts of laminin were similar. D-glucose (40 mM) tripled the amount of fibronectin incorporated into the endothelial cell/matrix layer (102 +/- 4 vs. 34 +/- 5 ng micrograms-1 DNA, P < 0.05), but had a lesser effect on pericytes. The non-metabolizable analogue L-glucose, also increased the amount of fibronectin incorporated in both pericyte and endothelial cell/matrix layers. The effects of D- and L-glucose on fibronectin secreted into the medium by both cell types were similar to the effects on incorporation of fibronectin into cell/matrix layers. Glucose had no effect on laminin synthesis. [35S]methionine radiolabeling and immunoprecipitation showed that pericytes and endothelial cells synthesize different forms of fibronectin. Both pericytes and endothelial cells synthesized an A and two B chains of laminin which were of similar apparent size, but the two cell types post-translationally modified the subunits differently. We conclude that pericytes and endothelial cells may contribute different forms and amounts of fibronectin and laminin to the retinal capillary basement membrane, so the preferential loss of pericytes in diabetes could result in basement membrane abnormalities which might lead to endothelial cell dysfunction.

Animals↗

PubMed1997

Retinal capillary pericyte apoptosis in early human diabetic retinopathy.

OBJECTIVE: To investigate the nature of retinal capillary pericyte dropout in early human diabetic retinopathy. METHODS: In the present study, neural retinas of 12 postmortem eyes from 6 patients (3 diabetic and 3 nondiabetic) were first fixed in buffered formaldehyde and then digested with trypsin. The preparations of trypsin-digested retinal blood vessels were stained with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) technique and then with perdiodic acid-Schiff technique (PAS), and counter-stained with hematoxylin to evaluate DNA fragmentation of cell nuclei and diabetic changes of retinal capillaries. RESULTS: TUNEL-positive apoptotic pericytes were observed in retinal capillaries in all three diabetic patients in this study. The TUNEL-positive pericytes were presented as darker stained cells with PAS-hematoxylin staining. A few TUNEL-positive retinal capillary endothelial cells were discovered in both eyes of one of the three diabetic patients. Neither TUNEL-positive pericytes nor positive endothelial cells were found in the three nondiabetic patients. A variety of typical diabetic microvascular changes were noticeable with PAS-hematoxylin staining in trypsin-digested retinal preparations from diabetic patients. These changes included thickened capillary walls, microaneurysms, "ghost-cell"-appearance of pericytes, acellular segments of capillaries, and a decreased ratio of retinal capillary pericytes to endothelial cells. All of these changes are characteristics of diabetic retinal microangiopathy. CONCLUSIONS: Retinal capillary pericyte apoptosis is a specific form of cell death which occurs during the early development of diabetic retinopathy. The significant decrease in the ratio of pericytes to endothelial cells and the predominant TUNEL-positive pericytes over endothelial cells suggest that a greater impact of apoptosis-related mechanisms occurs in pericytes than in endothelial cells and, thereby, a greater loss of pericytes takes place in early diabetic retinopathy. Apoptosis, therefore, is an important mechanism of pericyte dropout in the early diabetic retinopathy.

Aged↗

PubMed1998

Expression of apoptosis regulatory genes by retinal pericytes after rapid glucose reduction.

PURPOSE: Retinal capillary pericytes underwent apoptosis in vitro after they had been exposed long-term to high levels of glucose followed by a rapid glucose reduction. The present work was designed to study the expression of bcl-2 family members and apoptosis regulatory genes and to determine the status of oxidative stress induced by high concentrations of glucose in this in vitro apoptosis model. METHODS: Pericytes were grown in normal or high glucose concentrations (5, 20, 30, and 40 mM) for 10 days and then exposed to a rapid reduction of glucose to 0.5 mM or 5 mM. Pericyte cell death was evaluated by determining the loss of cell viability and the fragmentation of DNA using agarose gel electrophoresis. In parallel, the quantitative reverse transcription-polymerase chain reaction technique was used to determine the expression of bcl-2, bax, p53, and glutathione peroxidase (GSH-Px) genes. The intracellular level of glutathione (GSH) and the DNA fragmentation were determined simultaneously for pericytes treated with or without exogenous GSH monoethylester. Retinal capillary endothelial cells, experiencing the same glucose variation, were studied as a comparison. RESULTS: For pericytes, downregulation of bcl-2 was observed as early as 24 hours after rapid glucose reduction, whereas DNA fragmentation was not detectable at that time. After 72 hours, a decreased protein ratio of Bcl-2 to Bax was concomitant to evident loss of pericyte viability. During the period of high glucose and the following glucose reduction, p53 expression essentially was unchanged. Decreased levels of GSH induced by high concentrations of glucose (>30 mM) became further depleted when the glucose levels were rapidly reduced. Addition of GSH monoethylester to the medium restored the level of GSH in pericytes and prevented pericyte apoptosis induced by glucose variation. Moreover, the mRNA levels of GSH-Px were significantly elevated. By contrast, with the same glucose reduction endothelial cells did not undergo apoptosis. Their mRNA levels of bcl-2, bax, and GSH-Px essentially were unchanged. CONCLUSIONS: High levels of glucose and rapid reduction of glucose modulate the expression of bcl-2 family genes in retinal pericytes. Upregulation of GSH-Px and depletion of GSH indicate a reparative process of accelerated elimination of reactive oxygen species following rapid glucose reduction. These findings indicate that the aggravated oxidative stress and the weakened antioxidant defense induced by the combined effects of high levels of glucose and subsequent rapid glucose reduction cause pericyte apoptosis. Prevention of DNA fragmentation of pericytes by exogenous GSH further supports this notion. Because endothelial cells did not show similar pathologic changes, this proposed mechanism seems to be specific to pericytes.

Animals↗

PubMed2000

Role of pericytes in vascular calcification: a review.

Pericytes are defined by their location in vivo; the pericyte partially surrounds the endothelial cell of the microvessel and shares a common basement membrane with it. As an integral part of the microvasculature, pericytes play a fundamental role in maintaining local and tissue homeostasis. Current evidence also suggests that pericytes function as progenitor cells capable of differentiating into a variety of different cell types including osteoblasts, chondrocytes and adipocytes. It is now apparent that cells resembling microvascular pericytes, and termed 'pericyte-like' cells, have a widespread distribution in vivo. Pericyte-like cells have been identified in the inner intima, the outer media, and in the vasa vasora of the adventitia of large, medium and small human arteries (1, 2). Moreover, recent studies have suggested that these cells may be responsible, at least in part, for mediating the calcification commonly associated with atherosclerosis (1, 3, 4). In this review, we a) examine the evidence that microvascular pericytes deposit a bone-like mineralised matrix in vitro, b) compare the morphological and biochemical properties of microvascular pericytes, calcifying vascular cells (CVCs) and 'classical' smooth muscle cells (SMCs) isolated from bovine aorta, c) demonstrate that microvascular pericytes deposit a well-organised matrix of bone, cartilage and fibrous tissue in vivo, and d) discuss recent studies designed to gain a better understanding of how pericyte differentiation is regulated.

Animals↗

PubMed2005

Pigment epithelium-derived factor (PEDF) promotes growth of pericytes through autocrine production of platelet-derived growth factor-B.

Microvessels are composed of two types of cells, endothelial cells and pericytes. Pericyte loss or dysfunction participates in various types of disorders, including diabetic retinopathy. Recently, decreased levels of pigment epithelium-derived factor (PEDF) in the eye have been found to predict progression of diabetic retinopathy. However, the effect of PEDF on pericyte growth remains to be unknown. In this study, we investigated whether or how PEDF could stimulate proliferation of cultured retinal pericytes. PEDF stimulated DNA synthesis in pericytes in a dose-dependent manner. PEDF up-regulated pericyte mRNA levels of platelet-derived growth factor-B (PDGF-B). Down-regulation of PDGF-B gene expression by small interfering RNAs completely inhibited the PEDF-induced DNA synthesis in pericytes. Furthermore, PEDF increased protein kinase C (PKC) activity in pericytes and staurosporine, a potent cell-permeable inhibitor of PKC, completely blocked the PDGF-B gene induction and subsequent increase in DNA synthesis in PEDF-exposed pericytes. These results demonstrate that PEDF promotes the growth of cultured pericytes possibly through autocrine production of PDGF-B via PKC activation. Our present study suggests that PEDF could act as a mitogen or survival factor for pericytes, thereby being involved in the maintenance of retinal microvascular homeostasis.

Animals↗

PubMed2002

Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors.

Endothelial cells of tumor vessels have well-documented alterations, but it is less clear whether pericytes on these vessels are abnormal or even absent. Here we report that alpha-smooth muscle actin (alpha-SMA) and desmin-immunoreactive pericytes were present on >97% of blood vessels viewed by confocal microscopy in 100-microm-thick sections of three different spontaneous or implanted tumors in mice. However, the cells had multiple abnormalities. Unlike pericytes on capillaries in normal pancreatic islets, which had desmin but not alpha-SMA immunoreactivity, pericytes on capillary-size vessels in insulinomas in RIP-Tag2 transgenic mice expressed both desmin and alpha-SMA. Furthermore, pericytes in RIP-Tag2 tumors, as well as those in MCa-IV breast carcinomas and Lewis lung carcinomas, had an abnormally loose association with endothelial cells and extended cytoplasmic processes deep into the tumor tissue. alpha-SMA-positive pericytes also covered 73% of endothelial sprouts in RIP-Tag2 tumors and 92% of sprouts in the other tumors. Indeed, pericyte sleeves were significantly longer than the CD31-immunoreactive endothelial cell sprouts themselves in all three types of tumors. All three tumors also contained alpha-SMA-positive myofibroblasts that resembled pericytes but were not associated with blood vessels. We conclude that pericytes are present on most tumor vessels but have multiple abnormalities, including altered expression of marker proteins. In contrast to some previous studies, the almost ubiquitous presence of pericytes on tumor vessels found in the present study may be attributed to our use of both desmin and alpha-SMA as markers and 100-microm-thick tissue sections. The association of pericytes with endothelial sprouts raises the possibility of an involvement in sprout growth or retraction in tumors.

Actins↗

PubMed2003

Early contribution of pericytes to angiogenic sprouting and tube formation.

Immunostaining with endothelial and pericyte markers was used to evaluate the cellular composition of angiogenic sprouts in several types of tumors and in the developing retina. Confocal microscopy revealed that, in addition to conventional endothelial tubes heavily invested by pericytes, all tissues contained small populations of endothelium-free pericyte tubes in which nerve/glial antigen 2 (NG2) positive, platelet-derived growth factor beta (PDGF beta ) receptor-positive perivascular cells formed the lumen of the microvessel. Perfusion of tumor-bearing mice with FITC-dextran, followed by immunohistochemical staining of tumor vasculature, demonstrated direct apposition of pericytes to FITC-dextran in the lumen, confirming functional connection of the pericyte tube to the circulation. Transplantation of prostate and mammary tumor fragments into NG2-null mice led to the formation of tumor microvasculature that was invariably NG2-negative, demonstrating that pericytes associated with tumor microvessels are derived from the host rather than from the conversion of tumor cells to a pericyte phenotype. The existence of pericyte tubes reflects the early participation of pericytes in the process of angiogenic sprouting. The ability to study these precocious contributions of pericytes to neovascularization depends heavily on the use of NG2 and PDGF beta -receptor as reliable early markers for activated pericytes.

Animals↗

PubMed1995

Comparison of growth rates of bovine retinal and brain microvascular pericytes in different oxygen concentrations in vitro.

BACKGROUND: The hyperoxic injury of the microcirculation in the central nervous system appears to be specific to the retina in premature mammals. Oxygen tensions in normal adult mammalian retina and brain vary between nearly 0 and 90 mmHg. This study sought to compare the in vitro replication of retinal and brain microvascular pericytes in normal glucose medium and in 1%, 5% and 20% oxygen (equivalent to 15 mmHg, 35 mmHg and 150 mmHg, respectively). METHODS: A preliminary study, using oxygen microelectrodes, confirmed that the pericellular oxygen tension of pericytes, cultured in medium under air, was within 13 mmHg of the tension of the gas phase above the media. Pericytes were highly enriched by magnetic antibody cell sorting with the anti-pericyte monoclonal antibody (3G5) to 95% to 99% purity, to remove cell contaminants which may have invalidated the mitogenic assay. RESULTS: Mitogenic assays showed that brain pericytes replicated faster than their counterparts from retina (P < 0.0001, averaged for data from all culture conditions using three-way ANOVA). Reduction of oxygen tension from 150 to 15 mmHg led to significantly increased replication of retinal pericytes (P = 0.01), but an insignificant increase for brain pericytes. CONCLUSIONS: We have found that pericytes from the brain and retina cultured conventionally in fetal calf serum consume a relatively low amount of oxygen. Decreasing the oxygen tension to 1% (15 to 20 mmHg) increased the replication of retinal pericytes but not brain pericytes in normal glucose concentrations and in fetal calf serum. That retinal pericyte replication is sensitive to variation in oxygen tensions, indicates that the retinal microvascular cells have a unique biological response. This growth sensitivity to oxygen may be important in the pathogenesis of retinopathy of prematurity.

Animals↗

PubMed2001

Pericytes: cell biology and pathology.

Pericytes are perivascular cells with multifunctional activities which are now being elucidated. The functional interaction of pericytes with endothelial cells (EC) is now being established, using current molecular and cytochemical techniques. The detailed morphology of the pericyte has been well described. Pericytes extend long cytoplasmic processes over the surface of the EC, the two cells making interdigitating contacts. At points of contact, communicating gap junctions, tight junctions and adhesion plaques are present. Pericytes appear to show both structural and functional heterogeneity. The coverage of EC by pericytes varies considerably between different microvessel types and the location of pericytes on the microvessel is not random but appears to be functionally determined. Interaction between pericytes and EC is important for the maturation, remodelling and maintenance of the vascular system via the secretion of growth factors or modulation of the extracellular matrix. There is also evidence that pericytes are involved in the transport across the blood-brain barrier and the regulation of vascular permeability. The long-standing view that pericytes are the microvessel equivalent of larger vessel smooth muscle cells and are contractile is being reassessed using current methods. An important role for pericytes in pathology, and neuropathology in particular, has been indicated in hypertension, diabetic retinopathy, Alzheimer's disease, multiple sclerosis and CNS tumour formation.

Animals↗

PubMed1992

Behavior of postcapillary venule pericytes during postnatal angiogenesis.

Autogeneic bone marrow was implanted into an artificially created cavity in a segment of rat sciatic nerve, after removal of nerve fascicles, without damaging the epineurium or surrounding microcirculation. Under these conditions, the bone marrow induces capillary growth and forms granulation tissue from surrounding tissues, the behavior of pericytes being studied in the preformed (preexisting) postcapillary venules of the latter. Beginning 20 h after bone marrow implantation, the pericytes of the preexisting postcapillary venules hypertrophy, with shortening of their processes, prominent nucleoli, dispersal of ribosomes into their free form, fragmentation of basal lamina, and increased DNA synthesis. The number of contact surfaces between pericytes and endothelium is noticeably lower than in controls. Many pericytes are in mitosis. Cells with a shape transitional between pericytes and interstitial fibroblast-like cells appear. In some cases, Monastral Blue (MB) was used as a marker of the cells in preexisting venule walls of the graft bed. In the earlier stages of the experiment, the MB labelling is restricted to the cytoplasm of pericytes and endothelial cells of postcapillary venules, and to the macrophages that occur in the space between pericytes and endothelium. Furthermore, the marker continues to be observed, at a later stage, in some of the following cells: pericytes and endothelial cells of the newly formed vessels, macrophages migrating into the interstitium, transitional cells between pericytes and fibroblasts, and typical fibroblasts of the granulation tissue. The present study provides greater evidence that preformed microvasculature pericytes are substantially activated during postnatal angiogenesis and granulation tissue formation, suggesting that they may contribute to the origin of new pericytes and fibroblasts.

Aging↗

PubMed1987

Characterization of microvascular cell cultures from normotensive and hypertensive rat brains: pericyte-endothelial cell interactions in vitro.

We used specific markers and fluorescence microscopy to identify and characterize cerebrovascular cells. Cultures were derived from brain microvessels isolated from normotensive (Wistar Kyoto, WKY) and spontaneously hypertensive (SHR) rat brains prior to, coincident with and following the onset of chronic hypertension. Endothelial cells were characterized using di-acyl LDL and non-muscle isoactin-specific antibodies. Cerebrovascular pericytes were identified with the anti-muscle and non-muscle actin antibody staining. Using this combination of cell culture and fluorescence localization, we have been able to demonstrate that brain pericytes are tightly associated with the endothelial cells of the hypertensive-prone and hypertensive cell cultures, but not with the normotensive endothelial cultures. While the endothelial-pericyte ratio in the hypertensive-prone microvascular cultures was between 5:1 and 10:1, the number of pericytes associated with the hypertensive rat brain cultures increased two to five times (2:1-1:1). Muscle and non-muscle actin antibody staining localized the spindle-shaped pericytes of the hypertensive microvascular colonies. Pericytes were found overlaying and encircling the endothelial cells. Normotensive pericytes were not endothelial-associated. Whereas the hypertensive pericyte is devoid of stress fibers, the normotensive pericyte is a larger, spread-out cell possessing numerous stress fibers rich in muscle and non-muscle actin. These results provide the first evidence that the etiology and inception of cerebrovascular disease may be pericyte-related and suggest that pericyte contraction could play a pivotal role in regulating the flow of blood within the brain microcirculation.

Actins↗

PubMed2002

Pericytes and the pathogenesis of diabetic retinopathy.

Pericytes provide vascular stability and control endothelial proliferation. Pericyte loss, microaneurysms, and acellular capillaries are characteristic for the diabetic retina. Platelet-derived growth factor (PDGF)-B is involved in pericyte recruitment, and brain capillaries of mice with a genetic ablation of PDGF-B show pericyte loss and microaneurysms. We investigated the role of capillary coverage with pericytes in early diabetic retinopathy and the contribution to proliferative retinopathy using mice with a single functional allele of PDGF-B (PDGF-B(+/-) mice). As assessed by quantitative morphometry of retinal digest preparations, pericyte numbers in nondiabetic PDGF-B(+/-) mice were reduced by 30% compared with wild-type mice, together with a small but significant increase in acellular capillaries. Pericyte numbers were reduced by 40% in diabetic wild-type mice compared with nondiabetic wild-type controls. Pericyte numbers were decreased by 50% in diabetic PDGF-B(+/-) mice compared with nondiabetic wild-type littermates, and the incidence of acellular capillaries was increased 3.5-fold when compared with nondiabetic PDGF-B(+/-) mice. To investigate the effect of pericyte loss in the context of ongoing angiogenesis, we subjected mice to hypoxia-induced proliferative retinopathy. As a result, PDGF-B(+/-) mice developed twice as many new blood vessels as their wild-type littermates. We conclude that retinal capillary coverage with pericytes is crucial for the survival of endothelial cells, particularly under stress conditions such as diabetes. At high vascular endothelial growth factor levels, such as those in the retinopathy of prematurity model, pericyte deficiency leads to reduced inhibition of endothelial proliferation in vivo.

Animals↗

PubMed1996

Membrane voltage and whole-cell currents in cultured pericytes of control rats and rats with retinal dystrophy.

PURPOSE: Retinal vascular changes are associated with retinitis pigmentosa in man and the retinal dystrophy of the Royal College of Surgeons (RCS) rat. Recently we demonstrated that retinal capillary pericytes possess electrical membrane characteristics typical for smooth muscle cells and may thus regulate retinal blood flow in vivo. METHODS: In the present study we compared cultured pericytes of 5-7 day old RCS and control rats by measurement of membrane voltage (Vmem) with microelectrodes and currents with the whole-cell configuration of the patch-clamp technique. RESULTS: Resting membrane voltage (-37.6 mV +/- 1.0 mV, n = 106 and -36.6 mV +/- 0.7 mV, n = 102, respectively) and whole-cell currents, which are mainly determined by a potassium conductance, were comparable in pericytes of control and RCS rats. The electrogenic component of the Na(+)-K(+)-ATPase in RCS rat pericytes was reduced, because depolarization of their membrane voltage by Na(+)-K(+)-ATPase inhibitor ouabain (10(-4) mol.1-1 or K+ free solution was significantly decreased compared to control pericytes. Norepinephrine (10(-5) mol.1-1) depolarized Vmem of control rat pericytes by delta 7.0 mV +/- 1.3 mV (n = 7), whereas it hyperpolarized Vmem of RCS rat pericytes by delta 2.0 mV +/- 0.8 mV (n = 11). The depolarization of Vmem by histamine (10(-5) mol.1-1) was significantly reduced in pericytes of RCS rats (delta 2.6 mV +/- 0.4 mV, n = 7) compared to control pericytes (delta 4.3 mV +/- 0.5 mV, n = 6). In pericytes of RCS rats ATP-induced activation of inward and outward currents and depolarization of membrane voltage were also significantly reduced. CONCLUSIONS: The data indicate that there are differences in the electrophysiological properties of retinal capillary pericytes of 5-7 days old RCS and control rats. Whereas resting membrane voltage and K+ conductance are comparable in both groups, there are significant differences in the electrical activity of Na(+)-K(+)-ATPase and in the effects of vasoactive substances on the membrane voltage and currents. These differences might contribute to the vascular changes observed in RP, and possibly accelerate the progress of retinal dystrophy.

Adrenergic alpha-Agonists↗

PubMed1990

Pericyte coverage of retinal and cerebral capillaries.

We performed electron microscopic morphometric analyses on capillaries from macular and peripheral retinas of five adult cynomolgous monkeys and three elderly human subjects. Measurements from the monkey retinal capillaries were compared to those made on capillaries from frontal, temporal, parietal, and occipital cerebral cortex of the same animals. We measured the percent coverage of the endothelial lining of the capillaries by pericyte processes, as well as the ratio of the cytoplasmic areas of pericytes and endothelial cells. In addition, we compared the thickness of the capillary basement membranes in three regions: overlying pericytes; overlying endothelial cells; and interposed between pericytes and endothelial cells. In both monkey and human retinas, pericyte processes covered greater than 85% of the circumference of the capillary endothelial tube, whereas pericyte coverage of monkey cerebral capillaries was highly significantly (P less than 0.001) less than that of capillaries in either the macular or peripheral retina. The ratio of pericyte to endothelial cell cytoplasmic areas also was lower in the monkey cerebral cortex than in the retina, though the statistical significance was less than that of the length measurements. In all tissues measured, both from monkeys and humans, the portions of the capillary basement membranes interposed between pericytes and endothelial cells were highly significantly (P less than 0.0001) thinner than the regions of capillary basement membranes covering pericytes and endothelial cells. Considering functions that have been proposed for pericytes, these measurements suggest that regional control of microcirculatory flow and of blood-tissue barrier integrity, as well as control of endothelial cell proliferation, should be much greater in the retina than in the cerebral cortex. Thinner basement membranes between pericytes and endothelial cells may permit more cell membrane contacts between these cells, thus facilitating such control.

Aged↗

PubMed1984

Submicroscopic changes of cortical capillary pericytes in human perifocal brain edema.

Human brain capillary pericytes were studied by electron microscopy. Cortical biopsies from 17 patients with brain edema associated to brain trauma, tumors and congenital malformations were analysed. The data obtained in this study showed that pericytes like endothelial cells exhibited remarkable edematous changes, increased vacuolar and vesicular transport, formation of transient transpericytal channels and tubular structures, demonstrating pericyte brain barrier dysfunction. Images of normal and contracted pericytes showing shallow and deep nuclear invaginations, nuclear basal lamina, actin and myosin-like filaments and coupled interaction with endothelial cells through macula occludens were also encountered. Some pericytes displayed hypertrophic and necrotic changes. Phagocytic pericytes exhibited ingested erythrocytes. Hypertrophic pericytes inducing basement membrane splitting and degenerated pericytes with lacunar enlargement of endoplasmic reticulum, deposit of dense osmiophilic bodies and glycogen granules, vacuolization, hydropic changes of Golgi apparatus, and pleomorphic mitochondria were also found. Certain micropinocytotic vesicles seem to be orientated to multivesicular bodies suggesting that pericytes might play some role in edema resolution. Evidence of pericyte transformation into microglial cells or division into phagocytic cells and pericyte migration were not found.

Brain↗

PubMed1994

High glucose downregulates glucose transport activity in retinal capillary pericytes but not endothelial cells.

PURPOSE: To characterize the properties of the glucose transporters of bovine retinal capillary endothelial cells and pericytes and to determine the effects of increased glucose concentrations on glucose transport activity. METHODS: Primary cultures of bovine retinal capillary endothelial cells and pericytes were exposed to low and high glucose concentrations, and immunoblot analysis, 14C-3-O-methylglucose transport activity, and cytochalasin B binding assays were used to characterize the glucose transporters. RESULTS: GLUT1, but not GLUT3 or GLUT4 transporter isoforms, was present in plasma membranes isolated from each cell type. The EC50 for glucose transport was similar in endothelial cells and pericytes (3.94 to 0.48 mM versus 2.24 to 0.69 mM) and was consistent with the EC50 previously reported for GLUT1 transporters on other cells, as was the observation that insulin did not acutely stimulate glucose transport in either cell type. The Vmax for glucose transport was greater in pericytes than endothelial cells (71 to 25 versus 14.5 to 0.8 pmol/10 s/g DNA). Exposure of pericytes to 20 mM glucose for 8 days decreased the initial maximal rate of glucose transport by 30%, compared to pericytes cultured in 5 mM glucose (187 to 7 versus 133 to 9 fmol/20 s/g DNA, P < 0.01), but had no effect on glucose transport activity in endothelial cells. Culture in high glucose decreased the apparent amount of immunoreactive pericyte plasma membrane GLUT1 in immunoblots (0.611 to 0.055 versus 1.0 relative density units), decreased the binding of 3H-cytochalasin B to pericyte plasma membranes, and decreased the mRNA level for GLUT1 in pericytes by 25%. CONCLUSIONS: High-glucose concentrations downregulate glucose transport activity and GLUT 1 content in retinal capillary pericytes but not in endothelial cells. This effect occurred at a pretranslational level. The selective effects of high-glucose concentrations on retinal capillary pericytes in culture might be related to the selective effects of hyperglycemia on these cells in vivo.

3-O-Methylglucose↗

PubMed2003

Endothelial-pericyte interactions in angiogenesis.

It takes two to make blood vessels-endothelial cells and pericytes. While the endothelial cells are the better characterized of the two, pericytes are now coming into focus as important regulators of angiogenesis and blood vessel function, and as potential drug targets. However, pericytes are still surrounded by much controversy. They are difficult to define, they constitute a heterogeneous population of cells, and their ontogeny is not well understood. They are plastic and have the capacity to differentiate into other mesenchymal cell types, such as smooth muscle cells, fibroblasts and osteoblasts. Recent interest in pericytes also stems from their potential involvement in diseases such as diabetic microangiopathy, tissue fibrosis, cancer, atherosclerosis and Alzheimer's disease. The present review focuses on the role of pericytes in physiological angiogenesis. The currently favored view states that the initial endothelial tubes form without pericyte contact, and that subsequent acquisition of pericyte coverage leads to vessel remodeling, maturation and stabilization. Improved means of identifying and visualizing pericytes now challenge this view and show that high numbers of pericytes invest in actively sprouting and remodeling vessels. Genetic data demonstrate the critical importance of pericytes for vascular morphogenesis and function, and imply specific roles for the cell type in various aspects of angiogenesis.

Animals↗

PubMed2005

Pigment epithelium-derived factor inhibits oxidative stress-induced apoptosis and dysfunction of cultured retinal pericytes.

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis in the mammalian eye, suggesting that loss of PEDF is implicated in the pathogenesis of proliferative diabetic retinopathy. However, a role for PEDF in early diabetic retinopathy remains to be elucidated. Since oxidative stress is thought to be involved in pericyte loss and dysfunction, one of the changes characteristic of early diabetic retinopathy, we investigated whether and how PEDF could protect cultured retinal pericyte against oxidative stress injury. High glucose (30 mM) increased intracellular reactive oxygen species (ROS) generation in pericytes, which was completely blocked by PEDF. High glucose or H2O2 was found to induce growth retardation and apoptotic cell death of pericytes. PEDF completely restored these cytopathic effects on pericytes. An increased ratio of bax to bcl-2 mRNA level with subsequent activation of caspase-3 was observed in high-glucose- or H2O2-exposed pericytes, which was also completely prevented by PEDF. PEDF significantly increased glutathione peroxidase (GPx) mRNA levels and activity in pericytes. Further, PEDF was found to completely inhibit high-glucose- or H2O2-induced increase in a mRNA ratio of angiopoietin-2 to angiopoietin-1 and up-regulation of VEGF mRNA levels in pericytes. PEDF mRNA levels themselves were down-regulated in high-glucose- or H2O2-exposed pericytes. These results demonstrate that PEDF protects against high-glucose- or H2O2-induced pericyte apoptosis and dysfunction through its anti-oxidative properties via GPx induction. Our present study suggests that substitution of PEDF proteins might be a promising therapeutic strategy for treatment of patients with early diabetic retinopathy.

Animals↗