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Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:722-723

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:722.)
© 2001 American Heart Association, Inc.

Editorials

Adventitial Fibroblasts

Backstage Journeymen

Francis J. Miller, Jr

From the Department of Internal Medicine, University of Iowa, Iowa City.

Correspondence to Dr Francis J. Miller, Department of Internal Medicine, E314-4 GH, University of Iowa Hospitals, Iowa City, IA 52242. E-mail francis-miller{at}uiowa.edu


Key Words: adventitial fibroblasts

Although it has been 20 years since the acceptance of the endothelial layer as more than a hemostatic barrier in the blood vessel, the adventitia continues to be primarily considered a supporting structure, and its role in vascular disease has been easily dismissed. However, there is increasing support for the adventitia as a mediator of vascular dysfunction and a potential therapeutic target.1 2 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Shi et al3 report elevated superoxide levels in coronary adventitial fibroblasts within 1 day of balloon injury. The source of superoxide appears to be NAD(P)H oxidase.

The observation that adventitial fibroblasts generate reactive oxygen species (ROS) in response to vessel injury is not necessarily surprising. After injury, growth factors and cytokines are released from platelets and cell debris. NAD(P)H oxidase expression and superoxide production in fibroblasts increase within hours after exposure to angiotensin II.4 If vessel injury is severe and there is medial disruption, adventitial cells are activated, whereas when injury is mild, without rupture of the internal elastic membrane, adventitial activation is modest.5 6 These observations suggest that in response to endoluminal injury, locally released substances activate fibroblasts.

How can cells in the adventitia, which are relatively distant from the endothelium and subendothelial space, contribute to vascular dysfunction and neointimal formation? The findings of Shi et al3 suggest that increased adventitial superoxide levels after balloon injury may modulate fibroblast growth. Redox-mediated events in activated fibroblasts, which may include the release of a variety of paracrine substances and the stimulation of cell migration and proliferation, have the potential to markedly influence vascular function and structure.

Paracrine Effects

Superoxide levels rapidly increase in fibroblasts after vessel injury. Adventitia-derived superoxide can inactivate endothelium-derived NO7 and form the oxidant peroxynitrite. Perhaps more importantly, vascular cells, when activated, appear to secrete substances that can react with adjacent vascular cells, causing a "wave" of cell activation. Within hours after vascular injury, transforming growth factor-ß is secreted in the adventitia and may stimulate cell proliferation.5 8

After injury, the release of several paracrine substances by vascular cells may be modulated by increased cellular ROS. For example, in response to oxidative stress, smooth muscle cells secrete cyclophilin A, which causes extracellular signal–regulated kinase activation and cell growth.9 Within 24 hours after balloon injury, cyclophilin A is also detected in the adventitia.9 Secretion of cyclophilin A is inhibited by catalase, 4,5-dihydroxy-1,3-benzene disulfonic acid (Tiron), and diphenylene iodonium, all of which also inhibit fibroblast growth in serum.3 Several other proteins, including heat shock protein 90-{alpha}, are secreted by smooth muscle cells in response to oxidative stress and have been referred to as secreted oxidative stress–induced factors.10 Secretion of oxidative stress–induced factors may be a general response of vascular cells to injury, resulting in the recruitment of adjacent cells in the repair response.

Migration of Fibroblasts

After balloon injury, translocation of bromodeoxyuridine-labeled cells suggests that proliferating adventitial cells migrate to the neointima.5 This interesting observation was confirmed by implanting LacZ-positive fibroblasts into the adventitia of carotid arteries and tracking their migration from the adventitia, through the medial layer, and into the neointima after endoluminal injury.11 The relative proportion of smooth muscle cells and fibroblasts participating in neointimal formation after vascular injury remains unclear.

The mechanism by which adventitial fibroblasts migrate to the neointima after injury is not well characterized. Fibroblasts may migrate to the neointima across a chemotactic gradient. Selective injury to the adventitia, however, without endothelial disruption, is also associated with the formation of a neointima.12 Matrix metalloproteinases are necessary for the migration of cells into the neointima after vascular balloon injury.13 Adventitial expression of matrix metalloproteinases is increased after vascular injury and may facilitate the migration of fibroblasts to the neointima.2

Proliferation of Fibroblasts

Proliferating cells are evident in the adventitia on the day of vascular injury.14 The findings by Shi et al3 suggest that the proliferation of fibroblasts is dependent on ROS, especially H2O2. The observation that diphenylene iodonium inhibited fibroblast proliferation suggests a possible role for NAD(P)H oxidase in mediating cell growth. These observations are similar to the finding that growth of smooth muscle cells, in response to angiotensin II, is mediated by intracellular H2O2 derived from NAD(P)H oxidase.15

The role of ROS in vascular cell growth is only beginning to be understood. An increase in vascular cell ROS is not a general phenomenon resulting in unregulated activation of indiscriminate redox-mediated events. For example, although transfection of fibroblasts with either nox-1 or nox-4, which are different homologs of the NAD(P)H oxidase subunit gp91phox,16 increases NAD(P)H oxidase activity and superoxide generation, the consequences of overexpression of nox-1, compared with nox-4, are quite different. Fibroblasts proliferate after the overexpression of nox-1,17 but they undergo senescence with the overexpression of nox-4.18 It is not known whether compartmentalization of cellular ROS imparts specificity to this response.

Vascular Remodeling
Activation of adventitial fibroblasts induces the expression of {alpha}-actin and phenotypic modulation to myofibroblasts.2 Expression of contractile proteins in myofibroblasts may contribute to vascular remodeling by constricting vessels and contributing to late lumen loss.19 In addition, myofibroblasts are involved in tissue repair by deposition of extracellular collagen, which also contributes to vascular remodeling.2 20

Do the findings of Shi et al3 indicate that antioxidant therapy would prevent the fibroblast activation and proliferation in response to injury? Although oxidative stress is clearly increased in vascular injury, it has not been conclusively shown that antioxidants can prevent lesion formation.21 Antioxidants significantly decreased superoxide levels in balloon-injured vessels and promoted vessel remodeling but did not clearly affect neointimal size.22 23 The challenge is to identify the source of ROS within vascular cells, specifically, its compartmentalization or site of production, and the ability of injury to activate specific cell-signaling pathways. In the same way that an increase in ROS does not necessarily result in cell proliferation, a generalized reduction in tissue ROS may not "normalize" cell function.

The study by Shi et al3 reemphasizes the potential role of the adventitia in vascular disease. These data also add to the growing evidence that ROS contribute to the pathophysiology of blood vessel injury. Furthermore, because cells throughout the vessel wall appear to be involved in the response to injury, the adventitia is a novel potential therapeutic target.

References

  1. Gutterman DD. Adventitia-dependent influences on vascular function. Am J Physiol. 1999;277:H1265–H1272.
  2. Zalewski A, Shi Y. Vascular myofibroblasts: lessons from coronary repair and remodeling. Arterioscler Thromb Vasc Biol. 1997;17:417–422.[Free Full Text]
  3. Shi Y, Niculescu R, Wang D, Patel S, Davenpeck KL, Zalewski A. Increased NAD(P)H oxidase and reactive oxygen species in coronary arteries after balloon injury. Arterioscler Thromb Vasc Biol. 2001;21:739–745.[Abstract/Free Full Text]
  4. Pagano PJ, Chanock SJ, Siwik DA, Colucci WS, Clark JK. Angiotensin II induces p67phox mRNA expression and NADPH oxidase superoxide generation in rabbit aortic adventitial fibroblasts. Hypertension. 1998;32:331–337.[Abstract/Free Full Text]
  5. Shi Y, O’Brien JE Jr, Fard A, Mannion JD, Wang D, Zalewski A. Adventitial myofibroblasts contribute to neointimal formation in injured porcine coronary arteries. Circulation. 1996;94:1655–1664.[Abstract/Free Full Text]
  6. Christen T, Verin V, Bochaton-Piallat M-L, Popowski Y, Ramaekers F, Debruyne P, Camenzind E, van Eys G, Gabbiani G. Mechanisms of neointima formation and remodeling in the porcine coronary artery. Circulation. 2001;103:882–888.[Abstract/Free Full Text]
  7. Wang HD, Pagano PJ, Du Y, Cayatte AJ, Quinn MT, Brecher P, Cohen RA. Superoxide anion from the adventitia of the rat thoracic aorta inactivates nitric oxide. Circ Res. 1998;82:810–818.[Abstract/Free Full Text]
  8. Pawlowski JE, Taylor DS, Valentine M, Hail ME, Ferrer P, Kowala MC. Stimulation of activin A expression in rat aortic smooth muscle cells by thrombin and angiotensin II correlates with neointimal formation in vivo. J Clin Invest. 1997;100:639–648.[Medline] [Order article via Infotrieve]
  9. Jin ZG, Melaragno MG, Liao DF, Yan C, Haendeler J, Suh YA, Lambeth D, Berk BC. Cyclophilin A is a secreted growth factor induced by oxidative stress. Circ Res. 2000;87:789–796.[Abstract/Free Full Text]
  10. Liao DF, Jin ZG, Baas AS, Daum G, Gygi SP, Aebersold R, Berk BC. Purification and identification of secreted oxidative stress-induced factors from vascular smooth muscle cells. J Biol Chem. 2000;275:189–196.[Abstract/Free Full Text]
  11. Li G, Chen S-J, Oparil S, Chen Y-F, Thompson JA. Direct in vivo evidence demonstrating neointimal migration of adventitial fibroblasts after balloon injury of rat carotid arteries. Circulation. 2000;101:1362–1365.[Abstract/Free Full Text]
  12. Booth RF, Martin JF, Honey AC, Hassall DG, Beesley JE, Moncada S. Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation. Atherosclerosis. 1990;76:257–268.
  13. Bendeck M, Zempo N, Clowes AW, Galardy R, Reidy MA. Smooth muscle cell migration and matrix metalloproteinase expression after arterial injury in the rat. Circ Res. 1994;75:539–545.[Abstract/Free Full Text]
  14. Oparil S, Chen SJ, Chen YF, Durand JN, Allen L, Thompson JA. Estrogen attenuates the adventitial contribution to neointima formation in injured rat carotid arteries. Cardiovasc Res. 1999;44:608–614.[Abstract/Free Full Text]
  15. Ushio-Fukai M, Zafari AM, Fukui T, Ishizaki N, Griendling KK. p22phox is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem. 1996;271:23317–23321.[Abstract/Free Full Text]
  16. Lambeth JD, Cheng G, Arnold RS, Edens WA. Novel homologs of gp91phox. Trends Biochem Sci. 2000;25:459–461.[Medline] [Order article via Infotrieve]
  17. Suh YA, Arnold RS, Lassegue B, Shi J, Xu X, Sorescu D, Chung AB, Griendling KK, Lambeth JD. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999;401:79–82.[Medline] [Order article via Infotrieve]
  18. Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of Renox, and NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A. 2000;97:8010–8014.[Abstract/Free Full Text]
  19. Scott NA, Cipolla GD, Ross CE, Dunn B, Martin FH, Simonet L, Wilcox JN. Identification of a potential role for the adventitia in vascular lesion formation after balloon overstretch injury of porcine coronary arteries. Circulation. 1996;93:2178–2187.[Abstract/Free Full Text]
  20. Shi Y, O’Brien JE Jr, Ala-Kokko L, Chung W, Mannion JD, Zalewsik A. Origin of extracellular matrix synthesis during coronary repair. Circulation. 1997;95:997–1006.[Abstract/Free Full Text]
  21. Azevedo LCP, Pedro MA, Souza LC, de Souza HP, Janiszewski M, da Luz PL, Laurindo FRM. Oxidative stress as a signaling mechanism of the vascular response to injury: the redox hypothesis of restenosis. Cardiovasc Res. 2000;47:436–445.[Abstract/Free Full Text]
  22. Nunes GL, Sgoutas DS, Redden RA, Sigman SR, Gravanis MB, King SB III, Berk BC. Combination of vitamins C and E alters the response to coronary balloon injury in the pig. Arterioscler Thromb Vasc Biol. 1995;15:156–165.[Abstract/Free Full Text]
  23. Nunes GL, Robinson K, Kalynych A, King SB III, Sgoutas DS, Berk BC. Vitamins C and E inhibit O2- production in the pig coronary artery. Circulation. 1997;96:3593–3601.[Abstract/Free Full Text]



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Right arrow Oxidant stress

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