Histol Histopath (1991) 6: 269-286 Histology and Histopathology
Invited Revie W
Microvascular pericytes: a review of their morphological and functional characteristics
L. Diaz-Flores, R. Gutierrez, H. Varela, N. Rancel and F. Valladares Department of Pathology, Faculty of Medicine, La Laguna University, Canary Islands, Spain
Summary. A hundred years after the first description, Definition and identification niany aspects of pericytes reniain to be examined. Mesenchymal in origin, pericytes form an incomplete Mesoclcrmal in origin. the pel-icytes are extensively envelopment around the endothelial cells and within the branched cells located in the wall of nonniusc~~lar microvascular basement niernhrane of capillaries and microvesscls. c;~pillaries and postcapillary venules postcapillary venules. Morphologically. they appear as (Majno. 1965). where they form an incomplete long, slender, polymorphic cells. showing an elongated envelopment around the endothelial cells ancl within cell body, from which arise longitudinal and the microvascular basement membrane. circumferential branches. Cell bodies and cytoplasmic l'he morphological and topographical characteristics. processes of pericytes. as well as the endothelial cells, are the envelopment of the cell surface by basal lamina ancl enveloped by the same basal lamina. except for where the closc apposition of the tips of their processes to the they make direct contacts with each other. The pericytet underlying endotlieliuni can be used as a marker for the endothelial cell contacts are peg and socket. adlicsion identification of pcricytes in capillaries and postcapillary plaques and gap junctions. making up structural venule\. mechanisms for force transmission and a possible Pericyte\ were orig~nallydexribed hy Rouget (1873) receptor system for cells, in which the pcricyte and with the term adventitial cells, owing their current endothelial cells I-espond to secondary signals generated denomination to Zimmermann (1923). Ashton and De in the other cells. Electron niicroscopic studies have Oliveira ( 1966) have referred to the numerous terms revealed an elaborate network of cytoplasmic filaments. which have been used for these cells. such as pericytes Pericytc intermediate filament proteins show species and (Zimmerniann. 1023). adventitial cells (Rouget. 187.1). tissue differences. expressing vimentin or vimentin and Rouget cells,(Krogh, 19 19. 1929), mural cells (('ogan et desmin. The pericytes also express protein typical of al.. 196 1; Kuwabara and Cogan. 1963). pericapillary contractile cells, i.e. smooth muscle-specific isoforms of cells (Battig ancl Low. 1061), periendothelial cells and actin and myosin, cyclic GMP-protein kinase and perivascul;~rcells. Several reviews on the pericytes have tropomyosin. A gradual transition is observed between been undertaken. among which are those 61 Majno pericytes and smooth muscle cells in both terminal (1965) ancl Sims (1986). In this present revlcw, we a-terioles and venules. Several general functions for focused our attention on their morphological and the pericytes have been postulated: contractability: functional characteristics. permeability regulator: integrity maintainer; endothelial cell growth modulator; and cell progenitor with Incidence and distribution considerable mesenchymal potential. Pericytes arc an important cellular component of the Key words: Pericytes. Morphology, Function, nonmuscular or pericytic microvasculature: comparable Microvessels in position to smooth muscle cells in the media lavel- of arteries and veins (Fernando and Movat, 1964: ~ovat and Fernando. 1964). Indeed, pericyte cell bodies and cytoplasniic proccsscs are present in a majority of Offprint requests to: Dr. D. Lucio Diaz-Flores, Departamento de profiles in sections of capillaries and postcapillary Anatomia, Anatomia Patologica, Facultad de Medicina, Universidad vcnules (Forbes et al.. 1977). de la Laguna, Santa Cruz de Tenerife, lslas Canarias, Spain The relative frequency and distribution of pericytes Microvascular pericytes
appear to vary (Tilton et al., 1979a, 1983). Thus. the layers (Fig. ID). In conclusion, the shapes of pericytes number of pericytes and the pericyte coverage of are irregular and differ greatly depending on their microvessel circumference (pericytelendothelial cell location (Joyce et al.. 1984). Thus. on capillaries. the length ratio) show substantial differences depending on pericytes have a highly elongated perikaryon with long, topographical location. type of vessel (capillaries or slender processes, whereas on postcapillary venules they postcapillary venules) and stage of development. For have a less extended nuclear region with thicker and example, the retinal microcirculation of the rat has a more radial processes. much lower pericyte-to-endothelial cell ratio than that of the human. 1:3, 1:1, respectively (Cogan and Kuwabara. Basal lamina envelopment 1967; Tilton et al., 1985). In this order, the incidence of pericytes in ventricular vessels appears to be greater Cell bodies and cytoplasmic processes of pericytes, as than that in the atrial vessels of the heart of a mouse well as the endothelial cells, are enveloped by the same (Forbes et al., 1977). Also, the pericytes of the retinal basal lamina which is rich in amorphous, electron-dense microcirculation cover the capillary circumference much material. Both pericytes and endothelial cells contribute more extensively than those of the cerebral cortex to the formation of the basal lamina (Cohen et al., 1980). (Frank et al., 1987). Likewise, the surfaces of adult In the region where the basal lamina separates pericytes cortical capillaries are less extensively covered than from endothelial cells, several fenestrae are observed, those of immature capillaries in cerebral cortex during which permit direct contacts between these cells (Fig. 2) the embryonic development (Bar and Wolff, 1972). (Rhodin, 1968: Tilton et al.. 1979a: Sims, 1986). It has been demonstrated that the distribution of Although basal lamina is usually described as completely pericytes around microvessels exhibits specific polarities encircling the pericyte. except for where the tips according to the region of oxygen transfer, tending to be of pericyte processes are closely apposed to the concentrated in the non-gas exchange regions (Imayarna endothelium, it can be incomplete. Indeed. basal and Urabe. 1984: Sims. 1986). lamina may be absent in some regions between pericytes Several vascular channels. such as the sinusoids of and adjacent endothelial cells. the liver. spleen and bone marrow. or the renal The basal lamina surrounding the microvessels glomerular capillaries do not apparently have pericytes. increased in thickness with age and the range of Nevertheless, it is possible that Ito cells of liver, some microvessel wall thicknesses increased linearly according reticular cells of spleen and bone marrow. and mesangial to the amount of pericyte covering (Baker et al., 1971). cells of renal glomeruli are of the same developmental Nevertheless, a decrease in the number of pericytes with origin as pericytes (Fujimoto and Singer. 1987). increasing age in human cerebral white matter but not grey matter. has been described (Stewart et al., 1987). Morphological findings The role of pericyte glycosaminoglycan metabolism in the thickening and increase in porosity of the Configuration microvascular basement membrane of diabetics should be investigated (Stranirn et al., 1987). Although pericytes differ among species (Zimmerman. 1923). within different organs (Tilton et Surface contacts al., 1979b), and along the microvascular wall (Rhodin, 1967: Joyce et al., 1985b), in the present description. we Pericytes and endothelial cells are in close proximity will only take into account their general morphological and they make frequent direct contacts with each other characteristics. through interruptions in the basal membrane. The Morphologically. pericytes appear as long, slender pericytelendothelial contacts make up structural polymorphic cells located on the abluminal side of the mechanisms for force transmission and a possible endothelial cells (Fig. 1). In general. a single pericyte receptor system for cells in which the pericyte and covers two or four endothelial cells incompletely, endothelial cells respond to secondary signals generated showing an elongated cell body, nuclear region or in the other cells (Davies, 1986). In a study of isolated perikaryon, from which arises an elaborate system bovine retinal capillaries, potential 1013 periendothelial of longitudinal and circumferential branches contacts on a single endothelial cell were suggested (Zimmermann. 1923; Weibel. 1974). The nuclear region (Carlson, 1988a.b). The pericytelendothelial cell can be found immediately adjacent to the endothelium contacts show the different structural classes of junctions (Fig. lA), in a few cases protruding into the interstitial found among various cell types (Bruns and Palade, 1968; space (Figs. lB,lC), or contributing cytoplasmic Matsusaka. 1970: Spitznas and Reale, 1975: Edelman processes to more than one vessel. The branches make and Thiery, 1085: Sims, 1986: Carlson. 1989). such as peg up several major and smaller cytoplasn~icprocesses. The and socket (Leeson, 1979), adhesion plaques (Forbes et major processes are orientated- paralle.l to the long al.. 1977) and gap junctions (Simionescu et al.. 1975; vascular axis and the smaller ones partially encircle Cuevas et al. 1984: Nagy et al., 1984). In peg and socket the vessel wall. Although the pericytic covering of arrangements (Leeson, 1979), cytoplasmic processes of endothelial cells is incomplete, the cytoplasmic processes pericytes and endothelial cells interdigitate. Generally. of the pericytes sometimes overlap forming one or two cytoplasn~ic((fingers. of the pericytes insert themselves Fig. 1. Transmission electron photom~crographs showing some morphological and topographical characteristics of the pericytes In postcapillary venules. Cell bodies and cytoplasmic processes of pericytes (P) form an incomplete envelopment around endothelial cells (EC) and wlthin the microvascular basement membrane. The pericyte nuclear region can be found immediately adjacent to the endothelium (1A) or protruding into the interstitial space (16 and 1C). The cytoplasmic processes of the pericytes sometimes overlap forming two or three layers (ID). (Uranyl acetate and lead citrate. A X 8,500; B. C and D X 10,000) Fig. 2. Transmission electron photomicrographs show~ngper~cyte contacts. Cytoplasmic ccfingers,. of the per~cytesInsert themselves into deep endothelial cell invaginations (Figs. 2A, 28 and 2C, arrows) and cytoplasmic processes of endothelial cells in pericytes (Fig. 2D, arrow). Occasionally, pericyte processes touch each other (Fig. 2E, arrow). P: Pericyte. EC: Endothelial cells. (Uranyl acetate and lead citrate, A, B, C and D: X 14,000, E: X 10,000) Fig. 3. Ultrastructural characteristics of gradual transitional cell forms (TC) between pericytes (P) and smooth muscle cells in venules. Pericytes are observed in postcapillary venules (Figs. 3A and 36). Transitional cell forms in small venules showing a progressive increase in rnyofilaments, insertional dense plaques and dense bodies (Figs. 3C, 3D and 3E). EC: Endothelial cells. (Uranyl acetate and lead citrate, A, B and C: x 9,500, D and F: x 12,500) Fig. 4. Preformed postcapillary venules and capillar~esdur~ng anglogenesls. "Activated" per~cytes(P) are hypertroph~edand separated from the walls of parent vessels (Figs. 4A and 4B). Some of them in mitosis are also present (Figs. 4A, 4C, 4D, 4E and 4F, arrows). Semithin sections, Toluidine blue (X 850) Fig. 5. Bulg~ngand hypertrophied pericytes are observed in preformed postcap~llaryvenules dur~ngang~ogenesis. P: Pericytes. EC: Endothelial cell. In Fig. 5D an endothelial cell is in mitosis (arrow). (Uranyl acetate and lead citrate, X 12,000) Fig. 6. Transm~ss~onelectron photomicrographs of act~vatedper~cytes (P) ~n m~tos~s(F~gs. 6A and 66) and detached frorn the walls of parent vessels (Figs. 66 and 6C). The presence of basal lamina in interstitial cells has enabled them to be considered as pericytes. EC: Endothelial cells. (Uranyl acetate and lead citrate, A X 12,500, B x 11,000, C x 13,500) Fig. 7. Several photomicrographs showing arrival of pericytes at the growing capillaries. A cytoplasmic process of a per~cyttinserting into an endothelial cell (Fig. 7E). Figs. A, B, C (Semithin sections, Toluidine blue, X 850). Figs. D, E. (Ultrathin sections, Uranyl acetate and lead citrate, X 12,500) Microvascular pericytes
into deep endothelial cell invaginations (Figs. ?A. ?B. pericytcs. co~~rsingalo~~g tlie inner portion\ of tlic~r 2C) (Majno and Palade. 1961). Endothelial cell processes. even In the, 11104t clistill sites. Dense t?o~lic*4 invaginations into pericytes at-e much less frecl~~ently similar to those 01 \~iiootlirn~~sclc c~ll\ irncl ad1iesic.n observed (Fig. 2D). The adlicring plaques arc similar placl~~cs((Co~~rto!ancl lcs. IO8.T) 01. inscrtional dcn~c to desmosomes. In the gap junctions. tlie ac1,jacent placi~~eshctwec~~ mi~.~olil:~mcnt bunclles ancl den~e cellomembranes appear to fu5e clr are sep;11-;1tec1h! il material in the c\t~.acell~~l;~rmi~tris are present (Kliodi~l. 20 A space. 1968: Vegge. 1072: .filton et al.. 1'17')a). Fibronectin is present in areas of peric!,te-endothelial cell apposition, where fine cytoplasmic fibrils appear to Morphological variations insert themselves into the pericyte plasma membrane (Courtoy and Boyles, t983). This fact suggests a A\ has nlreacl! hccn \cc'n. ~)ericytesare polymorphc mechanical linkage between apposed cell sul-face\. cells ulio\e variations in elation to their anatomical and The pericyte processes do not frequently come into topographical di\trit)~~tio~iarc' considerably numerou,. contact with each other (Fig. ?E). and specialized For this reason. \ve shall onl! take into account certaln intercellular junctions between pericytes have not heen \pccific facts in the Central Ncr\;ous Sy\tcm. noted. Some authol-4 rcfes to two t!lpes of pcric!,tcs In Degeneration and loss of retina1 capillar!~ pericytes. cerebral mic~-ova\c~~lat~~~.c(Lafarga and Palacios. 1975: and selective disruption of pericytelendothelid cell Van Deurs. I97h: Mato and Ookawara. IOSI: Sumnc~.. contacts, are characteristic features of diabetic 1982: Jeyncs. 19Si). granular and agranular (Mato aud retinopathy (Cogan et al.. 1961; Kuwabara ancl Cogun. Ookawara. 1981: Jeync\. 1985). while other\ make no 1963; De Oliveira, 1966: Speiser et al.. 1968: Ashton and distinction (Far~.ell et al.. 1987: Castejtin. 1984: Tripathi, 1977; Sima et al.. 1985: Robinson et al.. 1989). Kristensson and Olsson. 1973: Le Beux and Willernot. Pericyte loss can occur as well in other capillary beds of 1980). The gran~~lartype is also termed gran~lleladen humans with diabetes (Tilton et al., 1981). These findings pliagocytic pericyte (Sumner. 1982). or pericyte wilh could lead to loss of capillary tone. resulting in dilatation. numerous primary and secondary Iysosomes (Lafarga formation of microaneurysms ancl angiogenic activity and Palacic,\. 1075). This type contains, as its name (Cogan and Kuwabara, 1967: Robinson et al.. 1989). indicates, autotluorcsccnt. dense. and PAS- and acid phosphatase-positi\c granules (Jeynes, 1985). The Structure agranular type, also termed .
intermediate filament proteins show species and tissue cyclic GMP - dependent protein kinrrse (Joyce et al., differences, expressing vimentin or vimentin and 1983) and tropomyosin (Joyce et al.. 1985a). desniin. This explains how, in some studies. pericytes The pericytes possess numerous high affinity specific and human hcmangiopericytomas were described as binding sites for the endothelin (Lee et al., 1990). The vinientin-positive, but desmin-negative (Roholl et al., endothelin, a peptide with potent vasoconstrictive 1986: Leader et al., 1987) while in others the pericytes action. is a regulator of the contractile properties of were found to contain both desmin and vimentin pericytes (Lee et al., 1990). (D'Amore et al.. 1983: Fujimoto and Singer. 1987). In the future. actin-binding proteins. alpha actimin, Indeed, renal pericytes express only vimentin in chicken, vinculin. filamin. etc. sho~~ldbe investigated in these whereas pericytes from other locations express vimentin cells (Joycc et al.. 1985b). although alpha actin and and desmin (Fujimoto and Singer. 1987). In lymph filamin appear to be in large concentrations in the nodes, pericytes of high endotheli~~mvenules express pericytes of cardiac muscle capillaries (Fujimoto and desmin in rats but not in humans (Toccanier-Pelte et al., Singer, 1987). 1987). During the sprouting of the capillaries, desmin- positive cells with the characteristics of pericytes were Related cells seen in connection with or encircled by the basal membrane of the newly formed vessels (Verhoeven and The pericytes are cells closely related to the vascular Buyssens, 1988). smooth muscle cells (Weibel, 1973: Stensaas, 1975: The pericytes possess actin microfilaments (Rhodin, Forbes et al.. 1977). Indeed, although the pericy~esshow 1962, 1968; Becker et al., 1967; Brightmann et al., morphological differences with the vascular smooth 1970: Weibel, 1973: Forbes et al., 1977; Le Beux and muscle cells, including those of configuration. nucleolar Willemot. 1978: Wallow and Burnside, 1980: Herman location. surface caveolae distribution, and quantity, and D'Aniore, 1983) with both smooth muscle and categories and stratification of intracellular filaments, a nonmuscle isoactins, which have been localized in situ gradual transition is observed between peric) tes and and in cell culture by immunofluorescence procedures sniooth muscle cclls in both terminal arterioles and (Hernian and D'Amore, 1985; Skalli et al., 1989). Thus, venules (Fig. 3) (Zimmermann, 1923; Krogh, 1923; besides the two isoforms, beta and gamma cytoplasmic Movat and Fernando, 1963; Majno. 1965; Stensaas, actin, found in the cytoplasm of virtually all cells, 1975; Forbes et al., 1977: Joyce et al.. 1983). For pericytes express some of the four so-called muscular instance, the transitional cell forms show a progressive actin isoforms. For instance, alpha smooth muscle actin increase in myofilaments, insertional dense placlues and has been demonstrated in cytoplasmic microfilament dense bodies (Figs. 3C. 3D. 3E). bundles of pericytes (Skalli et al.. 1989). This actin In some capill~~rieswhere pericytes do not exist, cells isoform is typical of smooth muscle cells and present in apposed to endothclial cells were shown to have some high amounts in vascular SMC (Gabbiani et al.. 1981: characteristics of pericytes (Fujinioto and Singel., 1987). Skalli et al., 1987). For example. Ito cells in the hepatic sinusoid and Nonmuscular actin (beta and gamma) is present reticular cells in thc splcnic sinusoid, contain tlie same within motile cytoplasm of the cortical regions, such distribution of dcsmin and vimentin as the pericytes, as membrane ruffes. lamcllae, spikes, pseudopodes and which would support rr relationship between both stress fibres, while muscle aclin seems to be localized (Fujimoto and Singer. 1987). in stress fibres, but not within other specific motile areas of pericyte cytoplasm (De Nofrio et al., 1989). When Origin pericyte stress fibres are completely dissolved by ionic detergent lysis, three actin isoforms have been quantified During tlie embryogenesis stage. the capillary-like to be present in rates of 1:2.*75:3 (a1pha:beta:gamma) vessels evolve progressively into vessels that are (De Nofrio et al.. 1989). surrounded by matrix and perivascular cells. During After description in the pericytes of thick filaments postnatal life angiogenesis, as in that of the granulation with morphological and solubility characteristics similar tissue. pericytes incorporate into the new capillaries. to those of niyosin (Le Beux and Willemot, 1978). In both cases. pericytes appear to be derived from isofc>rmsfor either sniooth muscle or nonmuscle myosin undifferentiated rncscnchymal cells (Clark ancl Clark, were observed in different proportions in the pericytes of 1975; Crocker et al.. 1970: Mikata et al., 1975; Saiki, capillaries and postcapillary venules (Joyce et al., 1978). 198%). Nonmuscle niyosin is present in a relatively high concentration in all capillary pericytes and absent in all Function smooth muscle cells (Joyce et al.. 198%). In the perieytes of small capillaries, the non-muscle isomyosin is the A hundred years after the first description. the predominant form, while in those of larger capillaries physiological significance of pericytes is still unclear and and postcapillaryvenules the sniooth muscle isomyosin is many aspects remain to be examined. Several functions present in a higher concentration. have been repeatedly presumed for them: a) contractile Pericytes also contain significant amounts of some cells, related to vascular smooth muscle, regulating proteins important for contraction regulation. such as venular and capillary permeability. and blood flow 280 Microvascular pericytes
(Zimmermann, 1913: Krogh. 1914; Rhodin. 1968: As regards the vascular permeability, some authors Forbes et al., 1977; Tilton et al., 1979b: Wallow and consider that the pericytes are the major contractile Burnside, 1980: Mazanet and Franzini-Armstrong. cells responsible for producing widening of the 1982); b) source of undifferentiated mesenchymal cells in interendothelial junctions in thc postcapillary venules repair and inflammation (Movat and Fernando, 1964; where the physiological events of inflammation occur Rhodin, 1968; Cliff, 1976); c) mechanical support and (Kelley et al.. 1988). Nevertheless. in the mechanism by stability to the vessel wall and endothelial cell growth which these gaps form. other authors involucrate abo~e and movement control; d) potcntial phagocytic capacity all. thc endothelial contraction. (Majno and Palade, 1961: Cancilla et al.. 1972: van Mesenchymal pluripotentiality Deurs, 1976); e) synthesis and transfer. Pericytes are considered by some author5 :IS Contractile capacity progenitor cells with great mesenchymal potential and, therefore. as a source of undifferentiated mcscnchymal From Rouget (1873), Zimmermann (1923) and cells for rcpiiir uncl inflammation (Cliff. 1963, 1970: Krogh (1929), it is accepted that pericytcs function as Mirra and Miles. 1981). However. the role of pericytes contractile elements within the microvasculature. during angiogenesis and granulation tissuc formation is The postulation that pericytes are contractile cclls is not clear (Schoefl. 1963: Cavallo et al., 1973: Ausprunk at present supported by the following: a) morphological and Folkman, 1977: Sholley et al.. 1977: McCracken et and topographical characteristics (Zimmermann, 1923: al.. 1979). Thus. some authors found labelling of DNA Krogh, 1924; Bruns and Palade, 1968; Forbes et al., with 3H-thymidine to be very slight in pericytes 2 days 1977; Mazanet and Franzini-Armstrong, 1982; Fujiwara after spinal corcl injury (Adrian, 1968: Adrian and and Vehara, 1984; Joyce et al.. 1984). as well as Williams, 1973). On the contrary, a high labelling presence of transitional cell forms, between pericytes response in pericytes or related cells has been noted in and smooth muscle cells (Zimmermann. 1923: Movat thc neovascularization in cornea induccd by chemical and Fernando. 1964); b) presence in pericytes of cautery (Burger and Klintworth, 1981), in subcutaneous an elaborate contractile apparatus and structural tissue after injection of live tumor cells (Cavallo et al. mechanisms for force transnlission from the former to 1972. 1973). in the skin following thermal injury (Sholley the endothelial cells: c) pericytes exprcss protein et al., 1977) ancl in several conditions which produce typical of contractile cells. i.e. smooth muscle-specific angiogenesis (Diaz-Flores and Dominguez. 1985; Diaz- isoforms of actin and myosin. cyclic GMP-protein Flores et al., 1990). Furthermore. several studies during kinase, tropomyosin. etc. (Joyce et al.. 1984. 1985a,b: angiogenesis have shown that <(activated. pericytes Herman and D'Amore. 1985: Fujimoto and Singer. hypertrophied and separated from the walls of parent 1987; Skalli et al 1989); d) observation of reduced vessels (Figs. 4, 5) (Ausprunk and Folkman. 1977; capillary diameter and selective bucking of endothelial McCracken et al.. 1979: Diaz-Flores et al.. 1990). Some cells beneath pericytes in response to vasoactive agents of these activated pericytes are also seen in mitosis (Figs. (Tilton et al.. 1979b): e) demonstrat~onof contractile 6A, 6B). In these stages, it can be difficult to distinguish response of cultured pericytes (Kelley et al., 1987). detached pericytes from interstitial fibroblasts (Burger Plasma and serum components appear to stimulate and Klintworth, 1981). although the presencc of basal pericyte contraction in whose mechanism actin filaments lamina in these interstitial cells has enabled them to be or stress fibres can act (Kelley et al., 1987). Histamine considered as pericytes (Figs. 6B,6C) (Cavallo ct al.. and serotonin both elicit pericyte contraction in vitro and 1972: McCracken et al., 1979). In spite of these beta-adrenergic agonists may act on pericytes to cause observations, little emphasis has been given to the vasodilatation (Kelley et al., 1988). possible role of the preexisting pericytes during Through their contractile activity. pericytes can angiogenesis. since the generally accepted theory is that. control the microvascular vasomotion (Tilton et al., during the sprouting of the capillaries, the new pericytes 1979a,b; De Nofrio et al.. 1989) and they contribute originate from interstitial undifferentiated mesenchymal to the regulation of capillary and venule blood flow cells. But it is also possible that the preexisting pericytes. and permeability (Rouget, 1873; Zimmermann. 1923; after migrating from the microcirculation, are a source Rhodin, 1967; Tilton et al. 1979b: Schor and Schor. 1986: of cells with high mesenchymal potential. which Kelley et al., 1987). Nevertheless, other authors have differentiate into other cell types, such as new pericytes, attributed the control of microvascular blood flow to vascular smooth muscle cells, arterial myointimal cells. endothelial contractility (Peck and Hoerr, 1951; Majno fibroblasts. chondroblasts. osteoblasts, preadipocytes et al., 1969; De Bruyn and Cho, 1974; Hammersen. and other mesenchymal cells in adult animals. 1980; De Clerk et al., 1981), or to a combination of In relation to the vascular smooth muscle cells, pericytes and endothelial cells (Rhodin, 1967). Studies of pericytes can have a role in the development of arteries the vascular wall cell contractility in vitro suggest that and veins from capillary vessels. Indeed, new capillaries pericytes are specialized for microvessel contraction form by sprouting and migration of endothelial cells which can generate a greater contractile force, but that from vessels of very small diameter. Construction of a endothelial cells may also contribute to microvascular larger vessel would require a lateral endothelial cell tonus (Kelley et al., 1987). proliferation and the presence of smooth muscle cells, Microvascular pericytes
possibly derived from capillary-associated pericytes. In multivariant path for cytoskeletal isoform function repair to injury of the rabbit aorta, adventitial perithelial during hemostasis or in association with inflammation cells (pericytes) are an apparent source of new medial and disease,,. sniooth muscle cells (Webster et al.. 1974). It has been If the pericytes have this capacity of retaining suggested that adventitial microcirculation can augment mesenchymal potential, then the progenitors for both the process of arterial intimal thickening from the new blood vessels and matrix-forming cells growing into cells present in the arterial wall by contributing a tissues undergoing repair would be found in the wall of supplementary population of cells. Indeed, under certain capillaries and postcapillary venules. In other words, it conditions, the myointimal cells of arterial intimal is possible that the pericytes and endothelial cells thickening seem to originate from the pericytes of intervene in an interrelated cellular repair system (Diaz- the adventitial microcirculation (Diaz-Flores and Flores et al.. 1990). In this case, not only are the small Dominguez, 1985; Diaz-Flores et al., 1990). In other venules the preferential target of inflammatory words, a possible explanation for the phenotypic mediators and the typical site of inflammatory cell similarities between pericytes and smooth niuscle cells is diapedesis, but also, an important source of endothelial that pericytes may be precursors of sniooth niuscle cells and matrix-forming cells during angiogenesis and repair. (Movat and Fernando, 1964: Rhodin, 1968). In relation to fibroblasts, it has been demonstrated, Stabilizer of the vessel wall using parabiotic rats, that wound fibroblasts arise from the adjacent perivascular connective tissue (Ross et al.. Intimate associations and interactions between 1970). Likewise, pericytes have been proposed as pericytes and endothelial cells intervene in the possible precursors of granulation tissue fibroblasts or maintenance of vascular integrity and in mediating the myofibroblasts (Crocker et al., 1970; Skalli and changes in morphology. motility, and metabolisn~of the Gabbiani, 1988), a .hypothesis consistent with the fact microvascular endothelial cells, as well as in endothelial that pericytes and certain subpopulations of cell growth control. These effects are modified during myofibroblasts share the same cytoskeletal feature)) angiogenesis (Figs. 4. 5. 6) (Kuwabara and Cogan, (Skalli et al.. 1989). It is considered that. when the 1963; Crocker et al., 1970) or in some diseases (Cogan et pericytes are transformed into fibroblasts and al., 1961; Buzney et al., 1977). When angiogenesis is myofibroblasts, the cells inhibit their ordinary blood flow developed, pericytes are incorporated into the wall of regulation and increase their secretory function, the newly formed vessels (Fig. 7). At this stage increasing their number of ribosomes and endoplasmic cytoplasmic processes of pericytes and endothelial cells reticula (Kobayasi and Serup, 1985). cave in on each other (Fig. 7F). This is evidence of a It has been hypothesized that the pericytes are the contact regularity phenomena between the pericyte and targets of bone growth or induction factors, which switch endotheliuni (Crocker et al., 1970). on their developmental pathway to prechondroblasts In this section we will take into account the role of and preosteoblasts. In this order. it has been pointed out pericytes in mechanical support of the vessel wall. that surrounding soft tissues may increase the process of endothelial cell growth control, and endothelial cell cartilage and bone regeneration from cells present in the movement control. perichondrium (Diaz-Flores et al., 1990) and periosteum (Diaz-Flores et al., 1990) by contributing inducible Mechanical support and stability to the vessel wall perivascular cells. In developing transplanted epididymal fat tissue of As has already been mentioned. pericytes can rats. slender perivascular cells resembling pericytes intervene as a mechanical support and as a stabilizer to appear to transform into preadipocytes (Iyama et al., the vessel wall. which is reinforced by the pericyte 1979). Also, after thermal lesion in the inguinal fat processes (Rhodin. 1968; Forbes et al.. 1977; Furchgott pad of rats. activated pericytes form fibroblast-like and Zawadski. 1980). For example, a higher density of cells that differentiate into adipocytes (Richardson et pericytes provides the microvessels with greater major al., 1982). resistence to damage by acute hypertension. On the Several pseudosarcomatous soft tissue lesions, contrary. loss of retina1 capillary pericytes in malignant fibrous histiocytoma and mixoid liposarcoma diabetic retinopathy could explain the occurrence of may originate from activated pericytes (Diaz-Flores et microaneurysms (Cogan et al.. 1961; Bloodworth, 1962: al.. 1990). Kuwabara and Cogan, 1963; Ashton and Tripathi, 1977; The in~n~unocytochemicalstudies are consistent with Sima et al., 1985; Robinson et al., 1989). the previous hypothesis. Thus, the presence of multiple contractile protein homologues is perplexing (Herman Endothelial cell growth control and D'Amore, 1985), but suggests the pericyte is adaptable and may reflect a pluripotential disposition of Pericytes can be responsible for inhibiting these cells (Herman and D'Aniore. 1985; Herman et al.. endothelial cell proliferation in quiescent capillaries 1987). Indeed, Herman et al. (1987) indicate that ccthis (Kuwavara and Cogan, 1963; Crocker et al., 1970) and seemingly unique ability of pericytes to coordinate therefore, they may be negative regulators of contractile protein gene expression may reflect a neovascularization (Kuwabara and Cogan, 1963; De 282 Microvascular pericytes
Oliveira. 1966; Crocker et al., 1970; Ausprunk and Weibel. 1974: Cancilla et al., 1972). Nevertheless, some Folkman, 1977; Feldman et al.. 1978). This role for the authors regard the pericytes as being incapable of pericyte is supported by the following: a) demonstration phagocytosis, while others ascribed a limited phagocytic in cocultures of endothelial cells with pericytes that the function to these cells. It is also considered that pericytes endothelial cell division is suppressed by the pericytes in are potentially phagocytic and become overtly so in a contact-dependent manner (Ordlidge and D'Amore, inflammatory reactions (Majno and Palade, 1961; 1987); b) vessels with the slowest EC turnover have the Cotran and Majno, 1964). highest extent of coverage by pericytes (Tilton et al., This property of the pericytes seems to play an 1985); c) there is an association between decreased important back-up role in the selectivity of the blood- numbers of pericytes and increased endothelial cell brain barrier (Broadwell and Saleman, 1981; Farrel et proliferation. observing that in several pathological al., 1987), limiting the passage of macromolecules conditions the neovascularization is associated with (Cancilla et al., 1972: van Deurs, 1976; Broadwell and pericyte loss; and d) there is a temporal relationship Saleman, 1981; Brierley and Brown, 1982; Sumner, between the cessation of microvessel growth and 1982; Heinsen and Heinsen, 1983; Bar and Budi- arrival of pericytes at the growing capillary (Fig. 7). Santoso, 1984; Jeynes. 1985). Indeed, in experimental Therefore, the pericytes may be negative regulators of and pathological conditions in which the blood-brain neovascularization and endothelial cell proliferation in barrier becomes leaky, pericytes are involved in the vivo (Kuwabara and Cogan, 1963; De Oliveira, 1966; phagocytosis of foreign proteins that pass the endothelial Crocker et al., 1970; Ausprunk and Folkman, 1977; layer, increasing the number of their lysosomes (Torack, Feldman et al., 1978). Furthermore, it has been 1961; Baker et al., 1971: Cancilla et al.. 1972; van Deurs, demonstrated in vitro that capillary endothelial cells 1976; Sumner, 1982). alone express all the information necessary to construct a new capillary. After capillary proliferation. pericytes The function of synthesis and the transfer of small appear to be important for growth control and regulation molecules of the capillary lumen. The inhibition or modulation of endothelial cell Pericytes play an important role in microvascular proliferation by the pericytes is not mediated by a stable basement membrane elaboration. They synthesize and diffusible factor and requires direct cell to cell contact secrete different classes of glycosaminoglycans in culture (Ordlidge and D'Amore, 1987). Therefore, the pericytel (Stramm et al., 1987). Also, it has been demonstrated endothelial cell contacts or close proximities offer a that cultured retina1 pericytes survive, proliferate and barrier to neovascularization. The inhibition of synthesize collagen (Cohen et al., 1980). endothelial cell proliferation is probably mediated by Junctional communication or transfer of small activated TGF-beta since, while EC and pericytes molecules between pericytes and microvascular cultured separately both secrete latent TGF-beta, the endothelial cells has been described (Larson et al., cocultures produce TGF-beta only in an active form, 1987). Furthermore, signalling between these cells is indicating that contact or close proximity between the achieved through gap junctions (Cuevas et al., 1984). cells is essential for the generation of activated The potential role of this activity in neovascularization TGF-beta. Immunoadsorption of coculture-derived has been previously considered. Intracellular conditioned media with antibodies to TGF-beta communication with other cells crossing the wall of eliminated the inhibitory activity' (Ordlidge and nonmuscular microvessels should be investigated. D'Amore, 1987,1988). 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