PROSTAGLANDIlVSLEUKOTRJENES ANDEBSEZVTIALFATTYACIDS Prostaglandins Leukottienes and Essential 0 Longman Group UK Ltd 1992

Fatty Auds

(1992) 47.93-99


Modulation of Prostacyclin Production by Cytokines in Vascular Endothelial Cells A. RistimZki*’ and L. Viinikka” *Children’s Hospital and ‘Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki. SF-00290 Helsinki, Finland (Reprint requests to LV) factors, monokines, and lymphokines (1 l), are important modulators of PG12 synthesis by vascular endothelium (Tables 1 & 2). Cytokines are released from aggregating platelets, from activated leukocytes, and from cells present in the vascular wall (Fig.), and both EC and smooth muscle cells have receptors for many of these agents (12-14). Thus, cytokines may be important modulators of blood vessel functions. The present review was written to clarify the roles of these peptides in regulating the production of PGIz and other prostanoids in vascular EC.

INTRODUCTION The luminal surface of all blood vessels is covered with a monolayer of endothelial cells (EC). The vascular endothelium interacts with the components of the blood and with other cells of the vessel wall and these interactions modulate the function of leukocytes, platelets, and smooth muscle cells (l-3). One function of the vascular endothelium is to adjust the blood flow by synthesizing a variety of biologically active substances that regulate blood coagulation, fibrinolysis, platelet adhesion and aggregation, and relaxation and contraction of blood vessels (l-3). The best known endotheliumderived antiplatelet and vasodilatory factor is prostacyclin (PGI,), which is the major arachidonic acid product of EC, except in some microvascular EC (3-5). In addition, PGI, inhibits the growth of human vascular smooth muscle cells in vivo (6), possibly by preventing the release of mitogens from macrophages, platelets, and EC (7), and by directly inhibiting smooth muscle synthesis of DNA (8). Furthermore, PGI, stimulates fibrinolytic activity in atherosclerotic patients (9) and inhibits foam cell formation and cholesterol accumulation in the vascular wall (7, 10). All this suggests that PGI, is an important antiatherogenic agent, yet little is known about how its production is regulated. However, recent data show that cytokines, which include polypeptide growth Table 1 Cytokines (PGI?) in HUVEC

that modulate production

of prostacyclin


Effect on PGI, production


Angiogenin EGF FGF acidic FGF basic IL-1 (a or 8) IL-2 TGF-a TGF-B TNF-a TNF-B VASIVEGF

Stimulatory Stimulatory Inhibitory Inhibitory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory

112 67 84.95-99 95 1%27,30-32 38 62 84 21, 22, 30,41 30 111

Interleukins and tumor necrosis factors Interleukin 1 (IL-l) is a single-chain polypeptide with a molecular weight (MW) of approximately 17 kD (15). Two IL-l gene products have been cloned, IL-la and IL-lb; they show limited structural homology, do not posses the signal sequence needed for a peptide to be secreted into the extracellular space, bind to the same receptor. and exhibit similar biological activities Table 2 Cytokines that modulate production of prostanoids vascular endothelial cells (EC) other than HUVEC Cytokine

Angiogenin EGF FGF acidic

FGF basic IFN-a IFN-y IL-1 (cc or p, IL-2 IL-6 TNF-a


Origin of EC

Bovine adrenal microvessels Canine fundic mucosal microvessels Bovine glomerular Bovine aorta and human retinal microvessels Bovine aorta and human retinal microvessels Bovine aorta Rabbit coronary microvessels Rat heart microvessels Rabbit coronary microvessels Human dermal microvessels Bovine aorta Bovine carotid artery Bovine pulmonary artery and bovine lung microvessels Human umbilical artery


Effect on prostanoid production


Stimulatory Stimulatory

112 68

Inhibitory Stimulatory

99 102



Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Stimulatory Inhibitory Stimulatory

47 33 48 33 34, 35 31. 38 39 42




Prostaglandins Leukotrienes and Essential Fatty Acids

GFs, IL-l, TGF-I3

Smooth musde eeU


Sources of cytokines that modulate prostanoid production in vascular endothelial cells.

(15, 16). These peptides are principally produced by activated macrophages, but other leukocytes, fibroblasts, vascular smooth muscle cells, and EC can also synthesize them (15). In addition, IL-1s are also associated with platelet membranes after thrombin activation (17). IL-1s mediate inflammation and many of their effects, including hypotension and fever, are dependent on prostanoid synthesis (15). Factors derived from activated human monocytes stimulated the production of PGI, and prostaglandin E, (PGE,) in human umbilical vein EC (HUVEC), in human and rat aortic smooth muscle cells and in human dermal fibroblasts (18, 19). This activity derived from monocytes was mimicked by purified human IL-l and was indistinguishable after separation by charge or by size fiom IL-l activity as measured by a bioassay for IL-l. Several groups have confirmed the stimulatory effect of IL-l on PG12 synthesis by HUVEC, using natural IL-l (20), human recombinant IL-la (20-24), and IL-l/3 (20, 22, 25-27). These different IL-l species are equipotent in stimulating EC prostanoid production (20, 22). IL-l stimulates synthesis of prostanoids in EC slowly, after incubation for several hours (19,23). When used for repeated treatments, IL-I shows no tachyphylaxis (25,26) in contrast to fast stimulators of prostanoid release, such as arachidonic acid, thrombin, and histamine (28, 29). In addition to increasing basal production of prostanoids in HUVEC (18, 19) preincubation with IL- 1 enhances the thrombin- and histamine-induced rapid release of PGI,, PGE,, and PGF2, (25, 30, 31). Furthermore, IL-l increases endogenous release of arachidonic acid (25) enhances recovery of PG12 synthesis after the irreversible inhibition of cyclooxygenase by aspirin (25), upregulates the expression of cyclooxygenase

mRNA at transcriptional level (24, 32), increases the amount of immunoreactive cyclooxygenase (32), and stimulates the fast release of PG12 induced by arachidonic acid (25) and PGH, (30). These results suggest that, at least in HUVEC, IL-l stimulates the activity of phospholipase AZ, cyclooxygenase, and PGIZ synthase, i.e. all the enzymatic steps involved in the synthesis of PG12. IL-l stimulates PGI, and/or PGE, production, not only in HUVEC, but also in EC from rabbit coronary microvessels (33) and in human dermal microvascular EC (34). IL-2 is a secretory peptide of T lymphocytes with a MW of approximately 15 kD and it binds to a receptor of its own (36). In contrast to an earlier finding by Rossi et al (19), IL-2 stimulates PGIZ production in an RNA and protein-synthesis-dependent manner, enhances the recovery of PGI, production after aspirin treatment, and increases the amount of immunoreactive cyclooxygenase in bovine aortic EC and/or in HUVEC (37, 38). IL-6 is a secretory peptide with a MW of between 23-30 kD, which binds to a receptor of its own (36). It is produced by a wide variety of cells, including macrophages, T and B lymphocytes, and EC. IL-6 inhibits production of PGI, in bovine carotid artery EC at the cyclooxygenase level (39), but does not affect PGI, synthesis in HUVEC (40). Tumor necrosis factor a (TNF-o, also known as cachectin) is, like IL-l, a single-chain polypeptide with a MW of approximately 17 kD, a product of activated macrophages, a mediator of inflammation, and it possesses no signal sequence (15, 16). Although IL-l and TNF-a have many biological activities in common (including prostanoid dependent hypotensive and pyrogenie effects), they are not structurally related and they

Modulation of Prostacyclin Production by Cytokines in Vascular Endothelial Cells

bind to separate receptors. TNF-a and the structurally related TNF-P (also known as lymphotoxin, which is a product of activated T lymphocytes and has a receptor with TNF-cl in common, (13)), stimulate synthesis of PGI? in HUVEC in a similar manner to although IL-l is more potent (21, 22, 27, 30,41). A combination of IL-l and TNF-a enhances PGI, synthesis additively (22). TNF-a also stimulates prostanoid synthesis in bovine pulmonary artery EC and in microvascular EC of bovine lung (42), but not in sinusoidal liver EC of guinea-pig (41). In a bovine EC line, TNF-a enhances phospholipase A? activity within minutes, which was suggested to be dependent on synthesis of a phospholipase AZ-activating protein (43). Interestingly, rapid release of PGI, was also found in human EC from umbilical arteries (44).

In terferons Three main types of interferon exist (IFN-a, IFN-p, and IFN-y) and their MWs are between 17-25 kD (45). IFNa, which actually is a group of several homologous peptides, and IFN-P share the same receptor, whereas IFN-y has a receptor of its own. IFN-a is most efficiently produced by activated macrophages, IFN-p by fibroblasts and epithelial cells, and IFN-)I by activated T lymphocytes (45), but IFN-a and IFN-P are also produced by EC (46). PG12 synthesis is stimulated by IFN-a in bovine aortic EC (47) and by IFN-y in rabbit coronary microvessel EC (33) and in rat heart microvascular EC (48). None of these IFNs had any effect on PGI? synthesis by HUVEC ( 19).

Epidermal growth factor and transforming growth factor-cc Epidermal growth factor (EGF) and transforming growth factor a (TGF-a) are single-chain polypeptides with MWs of approximately 6 kD (49, 50). Human EGF and TGF-cr have 42% amino acid sequence homology and both bind to the EGF receptor and stimulate an intrinsic tyrosine kinase (50, 51). EGF is abundant in human urine (also known as P-urogastrone), milk, saliva (49), and blood, in which it is stored in platelets and released from them in a cytoskeleton-dependent manner when the platelets aggregate (52-56). TGF-a is mainly a product of solid tumors (57) and embryonic tissues (58), and is produced by only a few cell types of nonmalignant adult human origin, such as keratinocytes (59) and macrophages (60). Although EGF and TGF-a bind to the same receptor with similar affinities, and many of their effects are the same, including induction of EC growth (61,62), TGF-a is more potent than EGF in increasing regional blood flow (63). in promoting angiogenesis (61). in accelerating wound healing (64), and in stimulating prostanoid-synthesis-dependent and -independent bone resorption (65. 66). EGF and TGF-a stimulate the synthesis of PGI, by HUVEC in a protein-synthesis-dependent manner. TGF-a being 10-100 times more


potent than EGF (62, 67). In addition, EGF stimulates synthesis of PGE? in canine fundic mucosal microvessel EC (68). and EGF-induced production of prostanoids may mediate its gastric mucosal protective activity in the rat (69, 70). EGF also enhances recovery of PGI? synthesis after aspirin treatment in rabbit aortas (71) and in cultured rat aortic smooth muscle cells (72).

TGF-/31 TGF-Pl is a homodimeric peptide with a MW of approximately 25 kD, which is the principal member of the TGF-P family of homologous peptides (73). This multifunctional peptide is synthesized by a variety of normal and transformed cells (74, 75). Human platelets contain TGF-Pl in large amounts (76, 77), and it is also released by macrophages and by EC (12, 14). Although TGF-Pl is usually liberated from cultured cells (78, 79) and human platelets (80) as an inactive compound, plasmin can activate a small pool of this latent molecule (81). Interestingly, TGF-Pl is activated in co-cultures of endothelial and smooth muscle cells or pericytes, probably by plasmin (82, 83). Thus, biologically active TGFp 1 may be present in the vascular wall, especially at sites of endothelial injury, where platelets are aggregating and plasmin is present. TGF-Bl stimulates production of PGIl in an RNA- and protein-synthesis-dependent manner in HUVEC, and EGF and TGF-Pl act synergistically (84). A similar synergism has been reported for prostanoid production in cultured mouse osteoblasts (85), an effect that correlates with the amount of immunoreactive cyclooxygenase, and in rat smooth muscle cells (86), an action accompanied with increased production of cyclooxygenase mRNA (87).

Fihroblast growth factors Acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF) (or heparin-binding growth factor-l and -2, respectively) are single-chain polypeptides with MWs of approximately 16 kD that activate through receptor binding intrinsic tyrosine kinase (88). There is a whole family of FGFs (88). but studies on EC have been made almost exclusively with either aFGF and bFGF. The latter is produced by macrophages. EC, and smooth muscle cells, whereas aFGF is found mainly in neural tissue (12, 14), and to some extent also in EC and vascular smooth muscle cells (89, 90). Both FGFs are potent angiogenic factors, but neither aFGF nor bFGF possesses the signal sequence needed for secretion of a protein into the extracellular space (88). This has led to the hypothesis that these FGFs may normally be present in a storage form, bound to heparin or heparin-like molecules attached to cell membranes or in the extracellular matrix. In fact, bFGF produced by EC is located in the matrix of these cells (9 1, 92). from which it is released by mechanical injury (93) or following degradation by proteases (94).


Prostaglandins Leukotrienes

and Essential Fatty Acids

aFGF or growth supplements containing it, especially in the presence of heparin, inhibit basal (84, 95-97) and agonist-induced (96,97) production of PGI, by HUVEC, as well as serum-induced recovery of PGI? production from aspirin treatment (98). In addition, aFGF inhibits basal and arachidonic acid-induced synthesis of PGE, in bovine glomerular EC (99). The effect of aFGF only appears after incubation for 24 h, and it reduces immunoreactive cyclooxygenase and PG12 synthase activity (97) and inhibits expression of cyclooxygenase mRNA (100). In our experiments, bFGF had no effect on endothelial PG12 synthesis during a 24-h incubation (84). This is somewhat unexpected, since bFGF is generally considered to be more potent than aFGF (12, 14, 88). On the other hand, incubation for 48 h with bFGF has been shown to inhibit PGI, synthesis in HUVEC (95). In addition, aFGF shifts the prostanoid production of the microvascular EC (but not that of bovine pulmonary artery EC) from PGI, to other prostanoids (101) and may do so in HUVEC (97). Interestingly, both aFGFand bFGF-stimulated PGI, release by fetal bovine aortic EC and by human retinal capillaries, although these cells did not respond to EGF, TGF-a, or TGF-/3 (102). Platelet-derived growth factor Platelet-derived growth factor (PDGF) is a dimeric molecule with a MW of approximately 30 kD, and is composed of A and B chains, which are assembled as homodimers or heterodimers that activate through a receptor binding intracellular tyrosine kinase (103). PDGF was originally purified from human platelets, but is now known to be produced by several other cell types including macrophages, smooth muscle, and EC (14, 103). Thus, PDGF is likely to be present at the site of a vascular injury. PDGF is a mitogen and it also enhances prostanoid production for many cell types, including fibroblasts and vascular smooth muscle cells (104-106). In contrast to an earlier finding with bovine aortic EC and bovine adrenal capillary EC (104), PDGF does not have an effect on PGI, production by bovine aortic EC (107, 108) or HUVEC (84, 108). This observation is compatible with the absence of PDGF receptors from large vessel EC (103, 109). On the other hand, microvessel EC have PDGF receptors, and PDGF is mitogenic for these cells (109, 110). It remains to be shown whether PDGF stimulates production of PGI, by capillary EC. Other cytokines Vasculotropin/vascular endothelial cell growth factor (VAS/VEGF, also known as vascular permeability factor) is a secretory peptide with a MW of 45 kD with homodimeric structure (111). VAS/VEGF is a member of the PDGF family but, unlike PDGF, it is a specific growth factor for vascular endothelial cells. VAS/VEGF stimulates PGI, synthesis in HUVEC, but only in very high concentrations (111).

Angiogenin is a 45 kD peptide with sequence homology to pancreatic ribonuclease (I 12). It is present in plasma at high concentration, is angiogenic in l~i\~, but does not induce proliferation of endothelial cells. Angiogenin stimulates fast release of PGI, by stimulating phospholipase AZ in EC from bovine adrenal microvessels and in HUVEC (112).

SUMMARY The data presented in this review clearly show that many different cytokines regulate the synthesis of PGI, in vascular EC (Tables 1 & 2). Since these agents are synthesized, stored, and/or released from platelets, leukocytes and cells present in the vascular wall (Fig.), they are to be found at sites of vascular injury and may, through their effect on the synthesis of PGI, and other prostanoids, regulate thrombogenesis and atherogenesis. Despite the mass of detailed data, the picture is still fragmentary. Very little, for instance, is known about the ‘orchestral effects’ of different combinations of cytokines. In addition, it seems that the regulation of PG12 synthesis by cytokines varies with the species and with the type of vasculature from which the cells originated. However, discrepancies may also be due to the use of different culture conditions. Moreover, we must remember that the present data are almost exclusively from in vitro studies, and the representativeness of these results in in vivo situations remains to be clarified. Acknowledgements AR is supported by the Finnish Academy. The valuable comments Professor Olavi Ylikorkala are gratefully acknowledged.

References 1. Jaffe E A. Cell biology of endothelial cells. Hum Pathol 18: 234-9, 1987. 2. Furchgott R F, Vanhoutte P M. Endothelium-derived relaxing and contracting factors. FASEB J 3: 2007-18. 1989. 3. Vane J R. linggtid E E, Botting R M. Regulatory functions of the vascular endothelium. N Engl J Med 323: 21-36. 1990. 4. Moncada S. Vane J R. Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A,. and prostacyclin. Pharmacol Rev 30: 293-331,1979. 5. Gryglewski R J, Botting R M, Vane J R. Mediators produced by the endothelial cell. Hypertension 12: 530-48, 1988. 6. Sinzinger H, Zidek T, Fitscha P, O’Grady J, Wagner 0. Kaliman J. Prostaglandin I2 reduces activation of human arterial smooth muscle cells in-vivo. Prostaglandins 33: 915-8. 1987. 7. Willis A L, Smith D L. Vigo C. Kluge A F. Effect of prostacyclin and orally active stable mimetic agent RS9342747 on basic mechanisms of atherogenesis. Lancet 2: 682-3, 1986. 8. Uehara Y, Ishimitsu T. Kimura K, Ishii M, Ikeda T. Sugimoto T. Regulatory effects of eicosanoids on thymidine uptake by vascular smooth muscle cells of rats. Prostaglandins 36: 847-57, 1988. 9. BertelC V, Mussoni L, Pintucci G, de1 Rosso G. Roman0


Modulation G, de Gaetano G, Libretti A. The inhibitory effect of aspirin on fibrinolysis is reversed by iloprost, a prostacyclin analogue. Thromb Haemost 61: 286-8, 1989. 10. Pomerantz K B, Hajjar D P. Eicosanoids in regulation of arterial smooth muscle cell phenotype, proliferative capacity, and cholesterol metabolism. Arteriosclerosis 9: 413-29. 1989. II. Nathan C. Spom M. Cytokines in context. J Cell Biol 113: 9816. 1991. 12. Joseph-Silverstein J. Rifkin D B. Endothelial cell growth factors and the vessel wall. Semin Thromb Hemost 13: 504-13, 1987. 13. Cotran R S. Pober J S. Effects of cytokines on vascular endothelium: their role in vascular and immune injury. Kidney Int 35: 969-75. 1989. 14. Klagsbmn M. Edelman E R. Biological and biochemical properties of fibroblast growth factors. Implications for the pathogenesis of atherosclerosis. Arteriosclerosis 9: 269-78, 1989. 15. Dinarello C A, Savage N. Interleukin- 1 and its receptor. Crit Rev Immunol9: l-20, 1989. 16. Rosenblom M G, Donato N J. Tumor necrosis factor ~1: a multifaceted peptide. Crit Rev Immunol 9: 2 144. 1989. 17. Hawrylowicz C M. Santoro S A. Platt F M, Unanue E R. Activated platelets express IL-l activity. J Immunol 143: 4015-18. 18. Albrightson C R, Baenziger N L. Needleman P. Exaggerated human vascular cell prostaglandin biosynthesis mediated by monocytes: role of monokines and interleukin 1. J Immunol 135: 1872-7, 1985. 19. Rossi V, Breviario F, Ghezzi P, Dejana E, Mantovani A. Prostacyclin synthesis induced in vascular cells by interleukin-1. Science 229: 174-6, 1985. 20. Dejana E, Breviario F. Erroi A, Bussolino F, Mussoni L. Gramse M, Pintucci G, Casali B. Dinarello C A, Van Damme I, Mantovani A. Modulation of endothelial cell functions by different molecular species of interleukin 1. Blood 69: 695-9, 1987. 21. Kawakami M, Ishibashi S. Ogawa H, Murase T. Takaku F, Shibata S. Cachectim’TNF as well as interleukin-1 induces prostacyclin synthesis un cultured vascular endothelial cells. Biochem Biophys Res Commun 141: 482-7. 1986. 22. Endo H. Akahoshi T, Kashiwazaki S. Additive effects of IL-1 and TNF on induction of prostacyclin synthesis in human vascular endothelial cells, Biochem Biophys Res Commun 156: 1007-14, 1988. 23 Rustin M H, Bull H A, Dowd P M. Effect of human recombinant interleukin-I alpha on release of prostacyclin from human endothelial cells. Br J Dermatol 120: 153-9, 1989. 24. Maier J A, Hla T. Maciag T. Cyclooxygenase is an immediate-early gene induced by interleukin- 1 in human endothelial cells. J Biol Chem 265: 10805-8, 1990. 25. Breviario F, Proserpio P, Bertocchi F, Lampugnani M G, Mantovani A, Dejana E. Interleukin- 1 stimulates prostacyclin production by cultured human endothelial cells by increasing arachidonic acid mobilization and conversion. Arteriosclerosis 10: 129-34. 1990. 26. Busso N. Huet S. Nicodeme E. Hiemaux J. Hyafil F. Refractory period phenomenon in the induction of tissue factor expression on endothelial cells. Blood 7X: 2027-35. 19Yi. 27. Dudley J D. LaMarche S, Mitchel M D. An endothelial cell model for the investigation of the molecular regulation of fetal vascular tone. Am J Obstet Gynecol 165: 1723-6, 1991. 28. Weksler B B. Ley C W. Jaffe E A. Stimulation of endothelial cell prostacyclin production by thrombin. trypsin. and ionophore A 23 187. J Clin Invest 62: 9X-30. 1978. 29. Baenziger N L, Fogerty F J. Mertr L F, Chemuta L F. Regulation of histamine-mediated prostacyclin synthesis in cultured human vascular endothelial cells. Cell 23: Y15-23, 1981. 30. Zavoico G B. Ewenstein B M, Schafer A I. Pober J S

of Prostacyclin


by Cytokines

in Vascular Endothelial


IL-1 and related cytokines enhance tbrombin-stimulated PGI? production in cultured endothelial cells without affecting thrombin-stimulated von Willebrand factor secretion or platelet-activating factor biosynthesis. J Immunol 142: 3993-9, 1989. 31. Bull H A, Dowd P M. Interleukin-1 potentiates histamine-induced release of prostacyclin from human endothelial cells. Br J Pharmacol 101: 703-9, 1990. 32. Wu K K. Sanduja R. Tsai A L, Ferhanoglu B, Loose M D. Aspirin inhibits interleukin l-induced prostaglandin H synthase expression in cultured endothelial cells. Proc Nat1 Acad Sci U S A 88: 2384-7, 1991. 33. Gerritsen M E. Eicosanoid production by the coronary microvascular endothelium. Fed Proc 46: 47-53, 1987. 34 Bull H A. Rustin M H, Spaull J, Cohen J, Wilson J E, Dowd P M. Pro-inflammatory mediators induce sustained release of prostaglandin Ez from human dermal microvascular endothelial cells. Br J Dermatol 122: 15364, 1990. 35 Bull H A. Cohen J. Dowd P M. Responses of human dermal microvascular endothelial cells to histamine and their modulation by interleukin 1 and substance P. J Invest Dermato197: 787-92, 1991. 36 Mizel S B. The interleukins. FASEB J 3, 2379-88,1989. 37 Hall E R. Papp A C. Seifert W J. Wu K K. Stimulation of endothelial cell prostacyclin formation by interleukin2. Lymphokine Res 5: 87-96, 1986. 38 Frasier-Scott K, Hatzakis H, Seong D, Jones C M, Wu K K. Influence of natural and recombinant interleukin 2 on endotheiial cell arachidonate metabolism. Induction of de novo synthesis of prostaglandin H synthase. .I Clin invest 82: 1877-83. 1988. 39. Mamo N. Morita I. Ishizaki Y, Murota S-I. Inhibitory effect of interleukin 6 on prostaglandin I2 production in cultured bovine vascular endothelial cells. Arch Biochem Biophys 292: 600-4, 1992. 40. Sironi M, Breviario F, Proserpio P. Biondi A. Vecchi A. van Damme J. Dejana E. Mantovani A. IL-1 stimulates IL-6 production in endothelial cells. J Immunol 142: 549-53. 1989. 41. Rieder H. Ramadori G, Allmann K-H. Mayer zum Buschenfelde K-H. Prostanoid release of cultured liver sinusoidal endothelial cells in response to endotoxin and tumor necrosis factor. Comparison with umbilical vein endothelial cells. J Hepatol 11: 35966. 1990. 42 Meyrick B. Christman B, Jesmok G. Effects of recombinant tumor necrosis factor-alpha on cultured pulmonary artery and lung microvascular endothelial monolayers. Am J Path01 138: 93-101, 1991. 43 Clark M A. Chen M J, Crooke S T, Bomalaski J S. Tumour necrosis factor (cachectin) induces phospholipase A? activity and synthesis of a phospholipase AZ-activating protein in endothelial cells. Biochem J 250: 125-32, 1988. 44 Langeler E G. Fiers W. van Hinsbergh V W M. Effects of tumor necrosis factor on prostacyclin production and the barrier function of human endothelial cell monolayers. Arterioscler Thromb 11:872-8 1, 199 1. 45. Balkwill F R. Interferons. Lancet 2.1060-3. 1989. 46 Einhort S. Elder A, Vlodavsky I. Fuks 2, Panet A. Production and characterization of interferon from endothelial cells. J Cell Physiol 122. 200--1. 1985. 47 Eldor A. Fridman R, Vlodavsky I, Hy A E. Fuks Z, Panet A. Interferon enhances prostacyclin production by cultured vascular endothelial cells. J Clin Invest 73: ‘51-7. 1984. 48. Mattila P, Renkonen R. Gamma-interferon induces prostacyclin and prostaglandin but not lipoxygenase product synthesis in rat endothelial cells. Immunol Lett 27: 59-63. 1989. 49. Carpenter G. Cohen S. Epidermal growth factor. Ann Rev Biochem 48: 193-216. 19’79. 50. Derynck R. Transforming growth factor-cc structure and biological activities. J Cell Biochem 32: 293-304. 1986. 51. Waterfield M D. Epidermal growth factor and related molecules. Lancer 1: 1343-6. 1989





and Essential Fatty Acids

52. Oka Y, Orth D N. Human plasma epidermal growth [email protected] is associated with blood platelets. J Clin Invest 72: 249-59, 1983. 53. Kurobe M, Tokida N, Furukawa S, Hayashi K. Some properties of human epidermal growth factor (hEGF) like immunoreactive material originating from platelets during blood coagulation. Biochem Biophys Res Commun 13: 729-33, 1986. 54. Savage A P, Chattejee V K, Gregory H, Bloom S R. Epidermal growth factor in blood. Regul Peptides 16: 199-206, 1986. 55. Pesonen K, Viinikka L, Myllyla G, Kiuru J, Perheentupa J. Characterization of material with epidermal growth factor immunoreactivity in human serum and platelets. J Clin Endocrinol Metab 68: 486-91, 1989. 56. Kiuru J, Viinikka L, Myllyla G, Pesonen K, Perheentupa J. Cytoskeleton-dependent release of human platelet epidermal growth factor. Life Sci 49,1997-2003, 1991. 57. Derynck R, Goeddel D V. Ullrich A, Gutterman J U, Williams R D, Bringman T S, Berger W H. Synthesis of messenger RNAs for transforming growth factors a and B and the epidermal growth factor receptor by human tumors. Cancer Res 47: 707-12, 1987. 58. Wilcox J N, Derynck R. Developmental expression of transforming growth factors alpha and beta in mouse fetus. Mol Cell Biol 8: 3415-22, 1988. 59. Coffey R J, Derynck R, Wilcox J N, Bringman T S, Goustin A S, Moses H L. Pittelkow M R. Production and auto-induction of transforming growth factor-cc in human keratinocytes. Nature 328: 817-20, 1987. 60. Rappolee D A, Mark D, Banda M J, Werb Z. Wound macrophages express TGF-a and other growth factors in vivo: analysis by mRNA phenotyping. Science 241: 708-12, 1988. 61. Schreiber A B, Winkler M E, Derynck R. Transforming growth factor-cc a more potent angiogenic mediator than epidermal growth factor. Science 232: 1250-53, 1986. 62. Ristimaki A. Transforming growth factor a stimulates prostacyclin production by cultured human vascular endothelial cells more potently than epidermal growth factor. Biochem Biophys Res Commun 160: 1100-5, 1989. 63. Gan B S, Hollenberg M D, MacCannell K L, Lederis K, Winkler M E, Derynck R. Distinct vascular actions of epidermal growth factor-urogastrone and transforming growth factor-a. J Pharmacol Exp Ther 242: 331-7, 1987. 64. Schultz G S, White M, Mitchell R, Brown G, Lynch J, Twardzik D R, Todaro G J. Epithelial wound healing enhanced by transforming growth factor-a and vaccinia growth factor. Science 235: 350-2, 1987. 65. Stem P H, Krieger N S, Nissenson R A, Williams R D, Winkler M E. Derynck R, Strewler G J. Human transforming growth factor-alpha stimulates bone resorption in vitro. J Clin Invest 76: 2016-9. 1985. 66. Ibbotson K J, Harrod J, Gowen M, D’Souza S. Smith D D, Winkler M E, Derynck R, Mundy G R. Human recombinant transforming growth factor a stimulates bone resorption and inhibits formation in vitro. Proc Nat1 Acad Sci USA 83: 2228-32, 1986. 67. Ristimlki A, Ylikorkala 0, Perheentupa J, Viinikka L. Epidermal growth factor stimulates prostacyclin production by cultured human vascular endothelial cells. Thromb Haemost 59: 248-50, 1988. 68. Chen M C, Sanders M J, Amirian D A, Thomas L P. Kauffman G, Sol1 A H. Prostaglandin Ez production by dispersed canine fundic mucosal cells. Contribution of macrophages and endothelial cells as major sources. J Clin Invest 84: 1536-49, 1989. 69. Amagase H. Murakami T, Misaki M, Higashi Y, Hashimoto K, Fuwa T, Yata N. Possible mechanism of gastric mucosal protection by epidermal growth factor in rats. Life Sci 47: 1203-l 1, 1990. 70. Konturek P K, Brozozowski T, Konturek S J, Dembinski A. Role of epidermal growth factor, prostaglandin, and sulthydryls in stress-induced gastric lesions. Gastroenterology 99: 1607-15. 1990.

71. Frazer C E, Ritter J M. Recovery of prostacyclin synthesis by rabbit aortic endothelium and other tissues after inhibition by aspirin. Br J Pharmacol 91: 251-6, 1987. 72. Bailey J M, Muza B, Hla T, Salata K. Restoration of prostacyclin synthase in vascular smooth muscle cells after aspirin treatment: regulation by epidennal growth factor. J Lipid Res 26: 54-61, 1985. 73. Massague J. The TGF-B family of growth and differentiation factors. Cell 49: 437-8, 1987. 74. Spom M B, Roberts A B, Wakefield L M, Assoian R K. Transforming growth factor-b: biological function and chemical structure. Science 233: 5324. 1986. 75. Spom M B. Roberts A B, Wakefield L M, de Crombrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol 105: 1039-45, 1987. 76. Childs C B, Proper J A, Tucker R F, Moses H L. Serum contains a platelet-derived transforming growth factor. Proc Nat1 Acad Sci USA 79: 5312-6, 1982. 77. Assoian R K. Komoriya A, Meyers C A, Miller D M. Spom M B. Transforming growth factor-p in human platelets. Identification of a major storage site, purifiction, and characterization. J Biol Chem 258: 7155-60, 1983. 78. Kryceve-Martinerie C, Lawrence D A, Crocher J, Jullien P, Vigier P. Further study of P-TGF released by virally transformed and non-transformed cells. Int J Cancer 35: 553-8, 1985. 79. Lawrence D A, Pircher R, Kryceve-Martinerie C, Jullien P. Normal embryo fibroblasts release transforming growth factors in a latent form. J Cell Physiol 121: 184-81984. 80. Pircher R. Jullien P, Lawrence D A. l%transfonning growth factor is stored in human blood platelets as a latent high molecular weight complex. Biochem Biophys Res Commun 136: 30-7. 1986. 8 1. Lyons R M, Keski-Oja J, Moses H L: Proteolytic activation of latent transforming growth factor-p from fibroblast-conditioned medium. J Cell Biol 106: 1659965. 1988. 82. Antonelli-Orlidge A, Saunders K B, Smith S R, D Amore P A. An activated form of transforming growth factor beta is produced by cocultures of endothelial cells and pericytes. Proc Nat1 Acad Sci USA 86: 4544-8, 1989. 83. Sato Y. R&in D B. Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-PI-like molecule by plasmin during co-culture. J Cell Biol 109: 309-15, 1989. 84. Ristim%ki A, Ylikorkala 0, Viinikka L. Effect of growth factors on human vascular endothelial cell prostacyclin production. Arteriosclerosis 10: 653-7. 1990. 85. Sumitani K. Kawata T, Yoshimoto T, Yamamoto S, Kumegawa M. Fatty acid cyclooxygenase activity stimulated by transforming growth factor-p in mouse osteoblastic cells (MC3T3-El). Arch Biochem Biopys 270: 588-95, 1989. 86. Pash J M, Bailey J M. Inhibition by corticosteroids of epidermal growth factor-induced recovery of cyclooxygenase after aspirin inactivation. FASEB J 2: 2613-8, 1988. 87. Bailey J M. Makheja A N. Pash J, Verma M. Corticosteroids suppress cyclooxygenase messenger RNA levels and prostanoid synthesis in cultured vascular cells, Biochem Biophys Res Commun 157: 1159-63, 1988. 88. Burgess W H. Maciag T. The heparin-binding (fibroblast) growth factor family of proteins. Ann Rev Biochem 58: 575-606, 1989. 89. Winkles J A, Friesel R, Burgess W H, Howk R. Mehlman T. Weinstein R, Maciag T. Human vascular smooth muscle cells both express and respond to heparin-binding growth factor I (endothelial cell growth factor). Proc Nat1 Acad Sci USA 84: 7124-8. 1987. 90. Mansson P-E, Malark M. Sawada H. Kan M, McKeehan













W L. Heparin-binding (fibroblast) growth factors type one and two genes are co-expressed in proliferating normal human vascular endothelial and smooth muscle cells in culture. In Vitro Cell Dev Biol 26, 209-12, 1990. Vlodavsky I, Folkman J. Sullivan R, Fridman R, IshaiMichaeli R. Sasse J, Klagsbrun M. Endothelial cellderived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc Nat1 Acad Sci USA 84: 2292-6. 1987. Flaumenhaft R. Moscatelli D. Saksela 0. Rifkin R B. Role of extracellular matrix in the action of basic fibroblast growth factor: matrix as a source of growth factor for long-term stimulation of plasminogen activator production and DNA synthesis. J Cell Physiol 140: 75-81. 1989. SatoY, Rifiin D B. Autocrine activities of basic fibroblast growth factor: regulation of endothelial cell movement. plasminogen activator synthesis. and DNA synthesis. J Cell Biol 107: 1199-205, 1988. Saksela 0. Rifkin D B. Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J Cell Biol 110. 767-75, 1990. Hasegawa N. Yamamoto M, Yamamoto K. Stimulation of cell growth and inhibition of prostacyclin production by heparin in human umbilical vein endothelial cells. J Cell Physiol 137: 603-7. 1988. Boutherin-Falson 0. Blaes N. Decreased prostacyclin production by human umbilical vein endothelial ceils cultured with endothelial cell growth factor and heparin. Thromb Res 54: 487-92. 1989. Weksler B B. Heparin and acidic fibroblast growth factor interact to decrease prostacyclin synthesis in human endothelial cells by affecting both prostaglandin H synthase and prostacyclin synthase. J Cell Physiol 142: 5 14-22, 1990. Hla T T. Bailey J M. Differential recovery of prostacyclin synthesis in cultured vascular endothelial vs. smooth muscle cells after inactivation of cyclooxygenase with aspirin. Prostaglandins Leukot Essent Fatty Acids 36: 175-84. 1989. Nitta K, Simonson M S. Dunn M J. The regulation and role of prostaglandin biosynthesis in cultured bovine glomerular endothelial cells. J Am Sot Nephrol 2: 15&63. 1991. Hla T, Maciag T. Cyclooxygenase gene expression is down-regulated by heparin-binding (acidic fibroblast) growth factor-i in human endothelial cells. J Biol Chem 266: 24059-63. 1991 Chung-Welch N. Shepro D. Dunham B. Hechtman H B.

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Prostacyclin and prostaglandin E? secretions by bovine pulmonq microvessel endothelial cells are altered by changes in culture conditions. J Cell Physiol 135: 224-34, 1988. Kuwashima L, Graeber J. Glaser B M. Stimulation of endothelial cell prostacyclin release by retina-derived factors. Invest Ophthalmol Vis Sci 29: 1213-20, 1988. Ross R. Platelet-derived growth factor. Lancet 1: 1179-82. 1989. Coughlin S R. Moskowitz M A. Zetter B R. Antoniades H N. Levine L. Platelet-dependent stimulation of prostacyclin synthesis by platelet-derived growth factor. Nature 288: 600-2. 1980. Coughlin S R. Moskowitz M A. Antoniades H N. Levine L. Serotonin receptor-mediated stimulation of bovine smooth muscle cell prostacyclin synthesis and it& modulation by platelet-derived growth factor. Proc Nat1 Acad Sci LJ S A 78: 7134-8. 1981. Habenicht A J R. Goerig M. Grulich J, Rothe D, Gronwald R, Loth U, Schettler G, Kommerell B. Ross R. Human platelet-derived growth factor stimulates prostaglandin synthesis by activation and by rapid de novo synthesis of cyclooxygenase. J Clin Invest 75. 13X1-7. 1985. Poggi A. Niewiarowski S, Stewart G J. Sobel E. Smith J B. Human platelet secreted proteins and prostacyclin production by bovine aortic endothelial cells. Proc Sot Exp Biol Med 172: 543-50, 1983. Callahan K S, Schorer A. Harlan J M. Platelet-derived growth factor does not stimulate prostacyclin synthesis by cultured endothelial cells. Blood 67: 13 14. 1986. Bar R S. Boes M. Booth B A. Dake B L. Henley S. Hart M N. The effects of platelet-derived growth factor in cultured microvessel endothelial cells. Endocrinology 124: 1841-8. 1989. Beitz J G. Kim I-S, Calabresi P. Frackelton R. Human microvascular endothelial cells express receptors for platelet-derived growth factor. Proc Nat1 Acad Sci USA 88: 2021-S. 1991 Bikfalvi A. Sauzeau C. Moukadiri H, Maclouf J. Busso N, Bryckaert M. Plouet J, Tobelem G. Interaction of vasculotropinivascular endothelial cell growth factor with human umbilical vein endothelial cells: binding, internalization. degradation, and biological effects. J Cell Physiol 149: 50-9. 1991. Bicknell R. Vallee B L. Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A,. Proc Nat1 Acad Sci USA 86: 1573-7. 1989.


Modulation of prostacyclin production by cytokines in vascular endothelial cells.

The data presented in this review clearly show that many different cytokines regulate the synthesis of PGI2 in vascular EC (Tables 1 & 2). Since these...
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