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PubMed2002

Angiogenesis of the blood-brain barrier in vitro and the function of cerebral pericytes.

Cerebral pericytes constitute an essential component of the blood-brain barrier (BBB) and are involved in blood vessel assembly. Recently, we reported on the induction of a BBB-specific enzyme expressed by cerebral pericytes (pericytic aminopeptidase N/pAPN) in coculture with cerebral endothelial cells. We completed this in vitro BBB system by adding astrocytes to these mixed cultures of endothelial cells and pericytes. Under these triculture conditions, endothelial cells and pericytes reorganize into capillary-like structures (CLSs). Capillary formation can also be achieved by the application of transforming growth factor beta 1 (TGF-b1) in the culture medium of endothelial-pericyte cultures lacking astrocytes. In contrast to the effect achieved by astrocytes, pericytes did not assemble with endothelial cells. In both cases (application of astrocytes or TGF-b1), endothelial cells underwent apoptosis. However, endothelial cells that form CLSs in the presence of pericytes appeared to be resistant to induction of apoptosis. On the basis of these observations, we concluded that astrocytes have a profound influence on the morphogenetic events underlying the organization of the vessel wall; that the effect of TGF-b1 is different from the astrocytic effect because it lacks induction of endothelial-pericyte association; and that pericytes stabilize CLSs formed by endothelial cells in coculture with astrocytes.

Animals↗
PubMed2004

Effects of angiotensin II on the pericyte-containing microvasculature of the rat retina.

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.

Alkaloids↗
PubMed2003

Receptor tyrosine kinase Axl modulates the osteogenic differentiation of pericytes.

Vascular pericytes undergo osteogenic differentiation in vivo and in vitro and may, therefore, be involved in diseases involving ectopic calcification and osteogenesis. The purpose of this study was to identify factors that inhibit the entry of pericytes into this differentiation pathway. RNA was prepared from pericytes at confluence and after their osteogenic differentiation (mineralized nodules). Subtractive hybridization was conducted on polyA PCR-amplified RNA to isolate genes expressed by confluent pericytes that were downregulated in the mineralized nodules. The subtraction product was used to screen a pericyte cDNA library and one of the positive genes identified was Axl, the receptor tyrosine kinase. Northern and Western blotting confirmed that Axl was expressed by confluent cells and was downregulated in mineralized nodules. Western blot analysis demonstrated that confluent pericytes also secrete the Axl ligand, Gas6. Immunoprecipitation of confluent cell lysates with an anti-phosphotyrosine antibody followed by Western blotting using an anti-Axl antibody, demonstrated that Axl was active in confluent pericytes and that its activity could not be further enhanced by incubating the cells with recombinant Gas6. The addition of recombinant Axl-extracellular domain (ECD) to pericyte cultures inhibited the phosphorylation of Axl by endogenous Gas6 and enhanced the rate of nodule mineralization. These effects were inhibited by coincubation of pericytes with Axl-ECD and recombinant Gas6. Together these results demonstrate that activation of Axl inhibits the osteogenic differentiation of vascular pericytes.

Animals↗
PubMed2003

Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors.

Tumor-infiltrating blood vessels deviate morphologically and biochemically from normal vessels, raising the prospect of selective pharmacological targeting. Current antiangiogenic approaches focus mainly on endothelial cells, but recent data imply that targeting pericytes may provide additional benefits. Further development of these concepts will require deeper insight into mechanisms of pericyte recruitment and function in tumors. Here, we applied genetic tools to decipher the function of PDGF-B and PDGF-Rbeta in pericyte recruitment in a mouse fibrosarcoma model. In tumors transplanted into PDGF-B retention motif-deficient (pdgf-b(ret/ret)) mice, pericytes were fewer and were partially detached from the vessel wall, coinciding with increased tumor vessel diameter and hemorrhaging. Transgenic PDGF-B expression in tumor cells was able to increase the pericyte density in both WT and pdgf-b(ret/ret) mice but failed to correct the pericyte detachment in pdgf-b(ret/ret) mice. Coinjection of exogenous pericytes and tumor cells showed that pericytes require PDGF-Rbeta for recruitment to tumor vessels, whereas endothelial PDGF-B retention is indispensable for proper integration of pericytes in the vessel wall. Our data support the notion that pericytes serve an important function in tumor vessels and highlight PDGF-B and PDGF-Rbeta as promising molecular targets for therapeutic intervention.

Animals↗
PubMed1999

Myosin translocation in retinal pericytes during free-radical induced apoptosis.

Vascular pathologies induced by ischemia/reperfusion involve the production of reactive oxygen species (ROS) that in part cause tissue injury. The production of ROS that occurs upon reperfusion activates specific second messenger pathways. In diabetic retinopathy there is a characteristic loss of the microvascular pericyte. Pericytes are more sensitive than endothelial cells to low concentrations of ROS, such as hydrogen peroxide (H(2)O(2)) when tested in vitro. Whether the pericyte loss is due to toxic cell death triggered by the noxious H(2)O(2) or apoptosis, due to activation of specific second messenger pathways, is unknown. During apoptosis, a cell's nucleus and cytoplasm condense, the cell becomes fragmented, and ultimately forms apoptotic bodies. It is generally assumed that apoptosis depends on nuclear signaling, but cytoplasmic morphological processes are not well described. We find that exposing cultured retinal pericytes to 100 microM H(2)O(2) for 30 min leads to myosin heavy chain translocation from the cytosol to the cytoskeleton and a significant decrease in cell surface area. Pericyte death follows within 60-120 min. Exposing cells to 150 mJ/cm(2) ultraviolet radiation, an alternate free radical generating system, also causes pericyte myosin translocation and apoptosis. Proteolytic cleavage of actin is not observed in pericyte apoptosis. 3-aminobenzamide, a pharmacological inhibitor of the cleavage and activation of the DNA-repairing enzyme poly (ADP-ribose) polymerase (PARP) inhibits pericyte apoptosis, and prevents myosin translocation. Deferoxamine, an iron chelator known to interfere with free radical generation, also inhibits pericyte myosin translocation, contractility, and cell death. Myosin translocation to the cytoskeleton may be an early step in assembly of a competent contractile apparatus, which is involved in apoptotic cell condensation. These results suggest that pericyte loss associated with increased free radical production in diabetic retina may be by an apoptotic phenomenon.

Animals↗
PubMed2002

Endothelin-induced changes in the physiology of retinal pericytes.

PURPOSE: Pericytes are positioned on the abluminal wall of capillaries and are thought to play a role in regulating retinal blood flow. Although endothelin (ET)-1 is a putative endothelium-pericyte signal, the mechanisms by which this molecule regulates pericyte function remain unclear. Because ion channels play a vital role in the response of pericytes to extracellular signals, this study was undertaken to assess the effects of ET-1 on ionic currents. METHODS: The perforated-patch configuration of the patch-clamp technique was used to monitor whole-cell currents of pericytes located on microvessels freshly isolated from the rat retina. To assay cell-to-cell coupling within retinal microvessels, a gap junction--permeant tracer was loaded through patch pipettes into pericytes and the spreading of the tracer detected by immunohistochemistry. RESULTS: ET-1 acting through ET(A) receptors altered pericyte currents and caused depolarization of the membrane potential. The effects on pericyte currents were dynamic over time. Initially, the nonspecific cation (NSC) and calcium-activated chloride (Cl(Ca)) currents were activated and the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) current inhibited. Subsequently, by a mechanism sensitive to a protein kinase C (PKC) inhibitor, the NSC, Cl(Ca), and voltage-dependent potassium currents diminished as gap junction pathways closed within the microvessels. CONCLUSIONS: ET-1 regulates pericyte conductances by multiple mechanisms. One process involves a PKC-dependent closure of gap junction pathways resulting in loss of electrotonic input from neighboring cells. Thus, ET-1 not only affects individual microvascular cells, but also regulates the effective size of the multicellular functional units that may serve to control capillary blood flow. This regulation of intercellular communication within pericyte-containing microvessels may be an important, previously unrecognized, action of ET-1.

Alkaloids↗
PubMed1994

Differential expression of alpha-actin mRNA and immunoreactive protein in brain microvascular pericytes and smooth muscle cells.

Hypertension has been linked to opening of the blood-brain barrier and may be related to the expression of the smooth muscle alpha-actin gene in contractile cells at the brain microvasculature. However, the cellular origin (i.e., endothelial cells, pericytes, smooth muscle cells) of the alpha-actin mRNA in the brain microvasculature is not clearly identified. Therefore, we investigated the abundance of actin mRNA by Northern blot analysis in isolated brain microvessels and in brain microvascular endothelial or pericytes in tissue culture. All samples showed the characteristic 2.1 kb transcript corresponding to cytoplasmic beta and gamma isoform mRNA. The 1.7 kb transcript corresponding to smooth muscle alpha-actin was detected in freshly isolated bovine brain microvessels, in primary cultures of brain microvascular pericytes, or endothelial cells; the latter cultures contain both endothelial cells and pericytes. The alpha-actin mRNA was absent in a cloned bovine brain endothelial cell line. The relative abundance of the alpha/(beta + gamma) actin transcript ratio was: cultured pericytes > freshly isolated microvessels > endothelial primary. The cellular distribution of the smooth muscle alpha-actin immunoreactive protein was studied by immunocytochemistry in cytospun/methanol-fixed isolated bovine brain microvessels with a monoclonal antibody directed to the amino-terminal decapeptide of the smooth muscle alpha-actin isoform. This antibody reacted strongly with precapillary arterioles of isolated microvessels, whereas no immunostaining was observed in either capillary endothelial cells or in pericytes. In conclusion, the alpha-actin mRNA is expressed in brain microvascular pericytes in tissue culture, but the immunoreactive alpha-actin protein is not expressed in brain microvascular pericytes in vivo. These data suggest that either 1) alpha-actin gene expression is induced in capillary pericytes in tissue culture or 2) alpha-actin mRNA in brain capillary pericytes in vivo is subject to translational repression resulting in no detectable alpha-actin protein under normal conditions.

Actins↗
PubMed1994

Heterogeneity of pericyte populations in equine skeletal muscle and dermal microvessels: a quantitative study.

The objective of this ultrastructural investigation was to determine if populations of pericytes in equine dermal and skeletal muscle capillaries increase in a head-to-foot direction, as has been reported in human skeletal muscles. Samples of equine microvessels were obtained from the longissimus dorsi skeletal muscle 150 cm. from the ground, from the dermis above this muscle, from the extensor carpi radiali muscle at 55 cm. from the ground, from the dermis adjacent to that muscle, and from dermis 15 cm. from the ground, just above the hoof wall. Tissues were processed for transmission electron microscopy. Electron micrographs were analyzed with a digitizing tablet and computer, to determine the ratios of endothelial cell outer circumference and pericyte inner lengths. Pericytes were separated into two classes; those closest to the endothelial cells were defined as covering capillaries. Those separated from endothelial cells by another layer of pericytes were termed enveloping pericytes. There was much greater coverage and envelopment of dermal capillaries (85% and 135%) than skeletal muscle capillaries (27% and 31%). Regression analysis of the pericyte coverage and envelopment of dermal capillaries revealed a significant increase in pericytes toward the ground. Similarly, the two skeletal muscle tissues differed significantly in their pericyte coverage and envelopment (25/27% at 150 cm., 31/35 at 55 cm.). The data indicate that, as in humans, capillary pericytes are not homogeneously distributed within the same tissues, but are more numerous closer to the ground. Differences in pericyte populations could affect studies of microvessel function.

Analysis of Variance↗
PubMed1994

Induction of alpha-smooth muscle actin expression in cultured human brain pericytes by transforming growth factor-beta 1.

Pericytes are cells localized at the abluminal side of the microvascular endothelium and completely enveloped by a basement membrane. Pericytes have close contact with endothelial cells and are probably involved in the regulation of endothelial cell functions. Previous studies suggested a role for pericytes in microvascular proliferation in tumors. To study this cell type, we isolated human brain pericytes from microvessel segments derived from autopsy brain tissue. These cells were characterized in vitro using a panel of monoclonal antibodies. Human brain pericytes were reactive with monoclonal antibodies directed against the high molecular weight-melanoma associated antigen and intercellular adhesion molecule-1, but only a minority of the cells expressed alpha-smooth muscle actin (alpha-SMA, 0 to 10%) or vascular cell adhesion molecule-1 (10 to 50%). In histologically normal human brain microvessels in situ, pericytes consistently lacked staining for these four markers. Tissue with microvascular proliferation, however, showed a marked pericyte staining for both alpha-SMA and high molecular weight-melanoma associated antigen. The expression of alpha-SMA in vitro could be slightly up-regulated by incubation with serum-containing medium. An increase in alpha-SMA expression up to 40% of the total cell population was seen when pericytes were treated with transforming growth factor-beta 1, whereas basic fibroblast growth factor slightly inhibited alpha-SMA expression. Incubation with other factors (platelet-derived growth factor-AA, heparin, interferon-gamma, tumor necrosis factor-alpha) had no effect on the alpha-SMA expression at all. Transforming growth factor-beta 1 thus induces smooth muscle-like differentiation in pericytes in vitro and might play a role in the activation of pericytes during angiogenesis in vivo.

Actins↗
PubMed1996

Pericytes in the microvasculature.

Pericytes, also known as Rouget cells or mural cells, are associated abluminally with all vascular capillaries and post-capillary venules. Differences in pericyte morphology and distribution among vascular beds suggest tissue-specific functions. Based on their location and their complement of muscle cytoskeletal proteins, pericytes have been proposed to play a role in the regulation of blood flow. In vitro studies demonstrating the contractile ability of pericytes support this concept. Pericytes have also been suggested to be oligopotential and have been reported to differentiate into adipocytes, osteoblasts and phagocytes. The mechanisms involved in vessel formation have yet to be elucidated but observations indicate that the primordial endothelium can recruit undifferentiated mesenchymal cells and direct their differentiation into pericytes in microvessels, and smooth muscle cells in large vessels. Communication between endothelial cells and pericytes, or their precursors, may take many forms. Soluble factors such as platelet-derived growth factor and transforming growth factors-beta are likely to be involved. In addition, physical contact mediated by cell adhesion molecules, integrins and gap junctions appear to contribute to the control of vascular growth and function. Development of culture methods has allowed some functions of pericytes to be directly examined. Co-culture of pericytes with endothelial cells leads to the activation of transforming growth factor-beta, which in turn influences the growth and differentiation of the vascular cells. Finally, the pericyte has been implicated in the development of a variety of pathologies including hypertension, multiple sclerosis, diabetic microangiopathy and tumor vascularization.

Animals↗
PubMed1997

Effect of CO2 on intracellular pH and contraction of retinal capillary pericytes.

PURPOSE: To test the potential participation of pericytes in the regulation of capillary blood flow according to metabolic needs. METHODS: The authors measured the change in extracellular pH (pHo), intracellular pH (pHi), and contractile tone of cultured bovine retinal pericytes when the ambient carbon dioxide (CO2) level was changed. RESULTS: Raising the partial pressure of CO2 (PCO2) from 5% to 10% or 20% acidified the medium, decreased the pHi, and relaxed the pericytes. Lowering the PCO2 from 5% to 0% or 2% alkalized the medium, raised the pHi, and contracted the pericytes. The reactions of pericytes in both cases were dose dependent. When the pHo was kept at approximately 7.4 as the PCO2 was changed by adjusting the ratio of NaHCO3 and NaCl in the medium (or by using HEPES buffer when PCO2 was zero), both elevating and lowering the PCO2 caused intracellular acidification but did not change the contractile tone of the retinal pericytes significantly. CONCLUSIONS: The effect of CO2 on the pHi and the contractility of pericytes is mediated primarily by its influence on the pHo. Elevation of CO2 causes pericytes to relax, whereas dispersion of CO2 causes pericytes to contract under the condition that allows pHo to be affected by PCO2. Therefore, pericytes may contribute to the regulation of local blood flow by their response to the change in local metabolic conditions.

Animals↗
PubMed2000

N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken.

Recruitment and adhesion of pericytes to endothelial cells represents a critical step in angiogenesis. We previously demonstrated the expression of neural (N)-cadherin at contact zones between pericytes and endothelial cells in embryonic chicken brain. To elucidate N-cadherin function in early angionenesis, we injected functionally blocking antibodies on embryonic days 4 and 5 into the tectal ventricle of chicken embryos. Brains were morphologically and immunocytochemically investigated on embryonic day 6. Blocking N-cadherin function resulted in defective pericyte adhesion, increased pericyte recruitment and disturbed vascular morphogenesis. Increased pericyte recruitment did not involve elevated pericytic proliferation. Concomitant disruption of ependymal adherens junctions and of endothelial-pericytic adhesion resulted in massive hemorrhaging in the basal forebrain, in misdirected endothelial sprouting, and ectopic vascularization. Morphological investigation of control embryos on embryonic days 4 and 5 indicated the initial involvement of pericytes in stabilization of angiogenic capillary sprouts. Together these results suggest that N-cadherin mediates adhesion, recognition, and signaling between pericytes and endothelial cells required for normal vascular morphogenesis.

Actins↗
PubMed2000

Aldose reductase inhibition prevents glucose-induced apoptosis in cultured bovine retinal microvascular pericytes.

The pathogenesis of pericyte loss, an initial deficit in the early stage of diabetic retinopathy, remains unclear. Polyol pathway hyperactivity has been implicated in the pathogenesis of diabetic retinopathy, and recent studies have suggested that apoptosis may be involved in pericyte loss. The present study was conducted to investigate whether high glucose induces apoptosis in cultured bovine retinal pericytes. The effect of an aldose reductase inhibitor, SNK-860, was also examined. After a 5 day incubation with various concentrations of glucose (5.5-40 m M) in the presence or absence of SNK-860, the cell viability and the percentages of dead cells were measured, and staining with the TUNEL method and Hoechst 33342, and DNA electrophoresis were performed. High glucose reduced the viability and increased the percentages of dead cells. TUNEL-positive cells were observed in pericytes under high glucose, but not in those under 5.5 m M glucose. In the staining of nuclei with Hoechst 33342, the percentage of apoptotic cells in total cells counted under high glucose was higher than that under 5.5 m M glucose. DNA electrophoresis of pericytes cultured with high glucose demonstrated a 'ladder pattern'. Hyperosmolarity also induced apoptosis in pericytes, but less than that by high glucose. SNK-860 inhibited the glucose-induced apoptosis in pericytes. These observations suggest that the pericyte loss in diabetic retinopathy involves an apoptotic process, and that the polyol pathway hyperactivity plays an important role in inducing apoptosis in pericytes by high glucose.

Aldehyde Reductase↗
PubMed2005

Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production.

The blood-brain barrier (BBB) is a highly organized multicellular complex consisting of an endothelium, brain pericytes and astrocytes. The present study was aimed at evaluating the role of brain pericytes in the induction and maintenance of BBB functions and involvement of transforming growth factor-beta (TGF-beta) in the functional properties of pericytes. We used an in vitro BBB model established by coculturing immortalized mouse brain capillary endothelial (MBEC4) cells with a primary culture of rat brain pericytes. The coculture with rat pericytes significantly decreased the permeability to sodium fluorescein and the accumulation of rhodamine 123 in MBEC4 cells, suggesting that brain pericytes induce and up-regulate the BBB functions. Rat brain pericytes expressed TGF-beta1 mRNA. The pericyte-induced enhancement of BBB functions was significantly inhibited when cells were treated with anti-TGF-beta1 antibody (10 microg/ml) or a TGF-beta type I receptor antagonist (SB431542) (10 microM) for 12 h. In MBEC4 monolayers, a 12 h exposure to TGF-beta1 (1 ng/ml) significantly facilitated the BBB functions, this facilitation being blocked by SB431542. These findings suggest that brain pericytes contribute to the up-regulation of BBB functions through continuous TGF-beta production.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Calcium influx pathways in rat CNS pericytes.

In central nervous system (CNS), pericytes have been proposed to play a role in broad functional activities including blood-brain barrier, microcirculation, and macrophage activity. However, contractile responses and Ca2+ signaling in CNS pericytes have not been elucidated. The aim of the present study is to investigate contractility and Ca2+ influx pathway in CNS pericytes. CNS pericytes were cultured from rat brain. Contraction of the pericytes in response to various stimuli was evaluated by the change in surface area measured by a light microscope with a digital camera. Reverse transcription and polymerase chain reaction (RT-PCR) was performed to examine the expression of mRNA of alpha-smooth muscle actin. Intracellular Ca2+ was measured using fura-2 fluorescence spectroscopy. A23187 (Ca2+ ionophore), high external K+ (4 x 10(-2) mol/l), endothelin-1, and serotonin induced contraction of CNS pericytes. RT-PCR analysis revealed the expression of alpha-smooth muscle actin in CNS pericytes. Cytosolic Ca2+ ([Ca2+]i) increased after application of high concentration of external K+, tetraethylammonium, and charybdotoxin, which was inhibited by nicardipine and removal of external Ca2+. Angiotensin-II, serotonin, acetylcholine, ATP, and endothelin-1 caused biphasic response in [Ca2+]i. In response to these agents, [Ca2+]i rapidly increased and then decayed to a relatively constant Ca2+ plateau. The Ca2+ plateau was partially inhibited by nicardipine and completely abolished by omission of external Ca2+. After intracellular Ca2+ store was depleted by the removal of external Ca2+ and addition of thapsigargin, reapplication of external Ca2+ evoked increases in [Ca2+]i. These results indicate that CNS pericytes express mRNA of alpha-smooth muscle actin and possess contractile ability. In CNS pericytes, resting membrane potential is regulated by large conductance Ca2+-activated K+ channels and Ca2+ enters into the cells via L-type voltage-dependent Ca2+ channels, agonist-activated Ca2+ permeable channels, and capacitative Ca2+ entry pathways.

Acetylcholine↗
PubMedDate not supplied

Electrotonic transmission within pericyte-containing retinal microvessels.

OBJECTIVE: Little is known about the electrotonic architecture of the pericyte-containing retinal microvasculature. Here, the authors focus on the cell-to-cell transmission of hyperpolarization, which can induce abluminal pericytes to relax and lumens to dilate. METHODS: With perforated-patch pipettes, the authors monitored the membrane potentials and ionic currents of pairs of pericytes located on freshly isolated rat retinal microvessels. Voltage changes were induced by administering electrical stimuli into pericytes, miniperfusing the KATP channel opener pinacidil, or using oxotremorine to activate chloride channels. RESULTS: Suggestive of extensive cell-to-cell communication, spontaneous voltage changes were strikingly similar in widely separated pericytes. In addition, injection of current into one of a pair of sampled pericytes always elicited a voltage response in the other sampled pericyte; the gap junction uncoupler, heptanol, blocked this transmission. In the dual recordings, hyperpolarization spreading from a current-injected pericyte decayed approximately 40% within 100 microm. In contrast, pinacidil-induced hyperpolarizations diminished by only approximately 2% in 100 microm. Depolarizations also appeared to spread with similar transmission efficacies. CONCLUSIONS: Based on the experiments, the authors propose that key features of the electrotonic architecture of retinal microvessels include highly efficient cell-to-cell communication within the endothelium and relatively inefficient transmission at pericyte/endothelial junctions. Thus, the endothelium is likely to provide an efficient pathway that functionally links contractile pericytes and thereby, serves to coordinate the vasomotor response of a retinal capillary.

Animals↗
PubMed2005

Endothelial survival factors and spatial completion, but not pericyte coverage of retinal capillaries determine vessel plasticity.

Pericyte loss and capillary regression are characteristic for incipient diabetic retinopathy. Pericyte recruitment is involved in vessel maturation, and ligand-receptor systems contributing to pericyte recruitment are survival factors for endothelial cells in pericyte-free in vitro systems. We studied pericyte recruitment in relation to the susceptibility toward hyperoxia-induced vascular remodeling using the pericyte reporter X-LacZ mouse and the mouse model of retinopathy of prematurity (ROP). Pericytes were found in close proximity to vessels, both during formation of the superficial and the deep capillary layers. When exposure of mice to the ROP was delayed by 24 h, i.e., after the deep retinal layer had formed [at postnatal (p) day 8], preretinal neovascularizations were substantially diminished at p18. Mice with a delayed ROP exposure had 50% reduced avascular zones. Formation of the deep capillary layers at p8 was associated with a combined up-regulation of angiopoietin-1 and PDGF-B, while VEGF was almost unchanged during the transition from a susceptible to a resistant capillary network. Inhibition of Tie-2 function either by soluble Tie-2 or by a sulindac analog, an inhibitor of Tie-2 phosphorylation, resensitized retinal vessels to neovascularizations due to a reduction of the deep capillary network. Inhibition of Tie-2 function had no effect on pericyte recruitment. Our data indicate that the final maturation of the retinal vasculature and its resistance to regressive signals such as hyperoxia depend on the completion of the multilayer structure, in particular the deep capillary layers, and are independent of the coverage by pericytes.

Angiopoietin-1↗
PubMed2007

Cytokine production in lipopolysaccharide-exposed rat lung pericytes.

BACKGROUND: Vessels of the pulmonary microvasculature are composed of two cell types: endothelial cells and pericytes. Pericytes are crucial to the development of capillary leak and pulmonary edema seen in acute respiratory distress syndrome (ARDS). Pericytes express toll-like receptor-4, and is upregulated in response to lipopolysaccharide (LPS). The objective of this study was to evaluate secretory cytokine production by rat microvascular pericytes. It is our hypothesis that pericytes secrete interleukin (IL)-1B, IL-6, and tumor necrosis factor (TNF)-A in response to LPS. METHODS: Rat lung pericytes (RLPs) were isolated and grown either alone or in coculture with rat endothelial cells. Cells from passages 3 to 5 were used and treated with LPS (control, 10 ng/mL, and 100 ng/mL) for varying amounts of time. Immunoblotting and reverse transcriptase polymerase chain reaction (RT-PCR) was used for detection and quantification of NF-kB. Enzyme-linked immunosorbent assay and RT-PCR were used for detection and quantification of cytokines. RESULTS: The protein and mRNA for NF-kB was detected in RLPs. Additionally, NF-kB mRNA increased with exposure to LPS. The supernatant of RLPs exposed to LPS contained IL-1B, and IL-1B increased in a time- and dose-dependant manner. An increase in mRNA for IL-1B, IL-6, and TNF-A was seen in a dose-dependant fashion. Cocultures produced significantly less IL-1B when exposed to similar concentrations of LPS. CONCLUSIONS: Pericytes contain the machinery necessary, and produce pro-inflammatory cytokines. Cocultures manufacture less IL-1B then pericytes alone, which is similar to previous coculture observations. Pericyte activation and cytokine production may play a role in capillary leak seen in gram-negative sepsis.

Animals↗