Gastroenterology
Volume 136, Issue 2 , Pages 400-403, February 2009

Is Inflammatory Bowel Disease a Vascular Disease? Targeting Angiogenesis Improves Chronic Inflammation in Inflammatory Bowel Disease

  • David G. Binion

      Affiliations

    • Inflammatory Bowel Disease Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
    • Corresponding Author InformationAddress requests for reprints to: Dr David Binion, Co-Director, Inflammatory Bowel Disease Center, Director, Translational Inflammatory Bowel Disease Research, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh School of Medicine, 200 Lothrop Street Mezzanine Level C Wing PUH, Pittsburgh, PA 15216; Tel: (412) 383-7486; Fax (412) 648-9378
    • ,
  • Parvaneh Rafiee

      Affiliations

    • Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin

published online 29 December 2008.

Article Outline

 

See “Endothelial caveolin-1 regulates pathologic angiogenesis in a mouse model of colitis” by Chidlow JH, Greer JJM, Anthoni C, et al on page 575; and “VEGF-A links angiogenesis and inflammatory bowel disease pathogenesis,” by Scaldaferri F, Vetrano S, Sans M, et al, on page 585.

“Next to leukocytes, the microvasculature and its endothelial lining play the most important role in inflammation.”

—Elie Metchnikoff, 1886 Nobel Laureate

Although the importance of the microvasculature in inflammation was first described >120 years ago by the Nobel Laureate Elie Metchnikoff, advances in endothelial and vascular biology have only begun to define the molecular and cellular basis for this understanding over the past 2 decades.1 This issue of Gastroenterology includes complementary manuscripts by 2 outstanding inflammatory bowel disease (IBD) vascular biology research groups who have provided insight into angiogenic mechanisms and the role of these pathophysiologic processes involving excess blood vessel growth in both human IBD and animal models of chronic gut inflammation. These 2 papers highlight the emergence of a more sophisticated understanding of chronic inflammation, where all cellular components of the intestinal tissues, including the microvascular endothelium, are being targeted for investigation as well as defining new potential routes for therapy.

Over the past 2 decades, the initial exploration of the vascular biology of IBD focused on the role of the microvascular endothelium as a “gatekeeper” of the inflammatory process, through the regulated interaction and recruitment of inflammatory cells into foci of inflammation. Endothelial cells will undergo activation in response to cytokines and bacterial products, thereby leading to cell adhesion molecule expression, enhanced leukocyte interaction, and the influx of the inflammatory infiltrate into tissues. Early exploration of these pathways in IBD revealed an increased expression of cell adhesion molecules, and selective recruitment of leukocytes binding the α4 integrin in the chronically inflamed intestine.2 Inhibition of α4 leukocyte interaction with ligands on the gut microvasculature in the Cotton-Top Tamarin, a new world primate that develops a spontaneous colitis in captivity, formed the basis for the development of selective leukocyte adhesion therapy.3 The anti-α4 inhibitor natalizumab ultimately received US Food and Drug Administration (FDA) approval for the treatment of refractory Crohn's disease in 2008.4, 5

Additional observations regarding leukocyte adhesion in human IBD have demonstrated enhanced and altered patterns of leukocyte binding, where naïve leukocytes are preferentially recruited into the IBD microvasculature, which is exposed to chronic inflammatory stress in vivo.6, 7 The ability to isolate human intestinal microvascular endothelial cells (HIMEC) has furthered our understanding of specific endothelial contribution to chronic inflammation in IBD.8, 9 HIMEC have been isolated routinely from normal margins of control patient bowel as well as from involved and uninvolved segments of IBD, and expanded in vitro to allow for specific experimentation and a mechanistic examination of endothelial activation in IBD.10 HIMEC isolated from both Crohn's disease and ulcerative colitis chronically inflamed bowel segments demonstrated an increased ability to bind leukocytes following inflammatory activation (interleukin-1β, tumor necrosis factor [TNF]-α, and lipopolysaccharide) compared with control HIMEC. This increase in leukocyte binding was an acquired phenomenon; endothelial cultures generated from paired segments of involved and uninvolved intestine demonstrated enhanced leukocyte binding only in areas exposed to chronic inflammation in vivo.11 This finding is all the more remarkable because the isolation strategies for human intestinal microvascular cultures can only generate small numbers of pure endothelial cells at the start of the culture, which will be passaged over the course of 6–8 weeks in vitro before having sufficient cell numbers for experimentation. Nevertheless, these disease-specific differences are maintained throughout the lifespan of the HIMEC culture, and have been present in multiple cell lines generated from multiple, unique patients over the past decade.

In addition to their central role in leukocyte recruitment, angiogenesis has emerged as an additional vascular mechanism contributing to chronic inflammation in IBD.12, 13, 14 The growth of new blood vessels in chronic intestinal inflammation has been always clinically apparent; surgeons operating on patients with Crohn's disease are guided by the neovascularization on the serosal surface of the bowel, which effectively demarcates “involved” segments of bowel. This neovascularization has been also readily apparent on imaging techniques, including microbubble enhanced ultrasound15 as well as computed tomographic enteroclysis, where increased vascular perfusion is a hallmark feature of increased bowel inflammation.16 However, the increased blood supply does not automatically equate with adequate perfusion of the intestine in IBD. One of the potential confounding areas in our understanding of the role of the microvasculature in IBD has been a series of observations from both human and animal models of IBD that suggest microvascular dysfunction and impaired perfusion of the mucosal surfaces affected by chronic inflammation. Intraoperative perfusion studies,17 endoscopic ultrasound,18 and intraoperative ultrasound19 of mucosal surfaces have all demonstrated impaired perfusion of the mucosal surfaces in chronically inflamed segments in Crohn's disease patients. This relative ischemia has also been observed in animal studies, where diminished perfusion at the level of the microcirculation has been demonstrated.20 Hatoum et al21 demonstrated in a series of ex vivo experiments on microvessels immediately isolated from surgically resected IBD bowel a profound loss of nitric oxide generation from the resistance arterioles, which have been exposed to chronic inflammation in vivo, thereby leading to microvascular dysfunction.21 This corresponds with observations in IBD HIMEC that have demonstrated that nitric oxide generation is impaired, and excess and sustained oxyradical generation is a commonly encountered finding in IBD endothelial cells.22 In addition to a loss of NOS2, there is increased expression of arginase II isoforms, which leads to a depletion of the substrate arginine, which is necessary for the generation of nitric oxide by the endothelium, and plays a central role in vasorelaxation.23 When one considers that tissue ischemia is one of the most potent stimuli for angiogenesis, then the increased vascularization on the outer surfaces of the bowel in conjunction with impaired perfusion at the mucosal surface owing to microvascular dysfunction may represent a compensatory process.

Angiogenesis is now recognized to play a critical role in various human disease processes, including cancer and chronic inflammation.24 The initial reports of angiogenesis being a component of human and animal models of IBD appeared during the past decade.12, 13, 14 Just how angiogenesis helps to perpetuate chronic intestinal inflammation is currently being defined. The concept that chronic inflammation requires an increased metabolic supply in the affected tissues, which must be provided by the augmented vascular supply, has formed one of the core concepts regarding angiogenesis and cancer, and may also be a component of angiogenesis in chronic inflammation. Likewise, the pathophysiologic neovascular beds arising from angiogenesis may contribute to altered leukocyte recruitment capacity for the chronically inflamed tissues. A third proposed mechanism regarding the contribution of angiogenesis to chronic inflammation is based on the fact that the endothelium is a dynamic cell population that can contribute to the milieu of cytokines and growth factors present in the chronically inflamed bowel.25

An additional mechanism that will be integrally linked with vascular endothelial growth factor (VEGF)-A–mediated angiogenesis has been explored by Scaldaferri et al26 in the present paper. Here the authors characterize the potential for increased vessel permeability and vascular leak to be found in chronically inflamed intestine. Using Evans blue dye as a marker of vascular permeability, these investigators demonstrated that transgenic mice overexpressing this molecule had increased leak into the gut tissues at baseline, which was markedly increased after the induction of DSS-induced colitis. When we consider the edema in bowel wall that accompanies chronic gut inflammation, VEGF-A–enhanced permeability will likely play a role in the “stiffness” that accompanies the remodeling of bowel in IBD, particularly Crohn's disease.27 This increase in interstitial fluid contributes to impaired perfusion dynamics, and potentially underlies the relative ischemia that accompanies chronic bowel inflammation. The contribution of hypoxia-inducible factors have recently received significant attention, and is likely a direct result of impaired perfusion secondary to VEGF-A–induced vascular leak.28, 29

The role of VEGF-A in IBD pathogenesis and inflammation induced angiogenesis is strengthened and defined in the present work by Scaldaferri et al.26 These authors show definitively that this angiogenic growth factor is increased in IBD patient tissues, mediates angiogenesis in the relevant population of endothelial cells (HIMEC), and plays a role in leukocyte recruitment through up-regulation of intercellular adhesion molecule 1, in addition to its capacity to increase vascular permeability. Importantly, they also demonstrated that the VEGFR2 seems to be the key receptor for VEGF-A in both human IBD and animal models, which paves the way for future therapies targeting this ligand in the treatment of chronic gut inflammation.

Sophisticated rodent models with targeted gene deletion in combination with DSS-induced colitis have allowed Chidlow et al30 to explore the fundamental mechanisms of endothelial signaling and angiogenesis in response to chronic intestinal inflammation. These authors have examined the function of caveolin-1, the major structural protein found in endothelial caveolae, in angiogenesis induced by chronic inflammation. In an elegant series of experiments using sophisticated rodent models of gene-deleted caveolin-1, they demonstrate that loss of this molecule in the endothelium prevents angiogenesis in the context of DSS colitis, resulting in a diminished chronic inflammation and less disease severity. Bone marrow transplant experiments confirmed that the expression of caveolin-1 must be present in the gut endothelium for angiogenesis to occur in the setting of chronic inflammation. Furthermore, these authors demonstrate that inhibition of angiogenesis significantly ameliorates chronic inflammatory damage to the bowel, linking angiogenesis with severity of the disease process. Although these authors did not specifically measure VEGF-A levels in their models, we can surmise from prior work, and the current studies by Scaldaferri et al, that the chronic inflammatory process would markedly increase this angiogenic factor. Thus, the endothelium must maintain the molecular mechanisms to respond to these signals, ultimately leading to the angiogenic process.

Our current IBD treatment approaches do not routinely target angiogenesis for therapy. To date, perhaps the best example of an antiangiogenic therapeutic trial in Crohn's disease has been a series of reports describing the beneficial effect of thalidomide in patients with refractory disease.31, 32 In addition to its capacity to function as a transcriptional inhibitor of TNF-α, thalidomide has documented antiangiogenic potential, which is felt to have been a central component of its teratogenicity, leading to phocomelia, severe birth defects, and fetal demise.33 Although thalidomide returned for clinical use through an extremely careful prescribing program, the long-term utility of this agent as a maintenance treatment strategy for chronic inflammation remains limited by a side effect profile that includes significant neuropathy. Many other agents with antiangiogenic potential, including cyclo-oxygenase-2 antagonists,34 interferon-α,35 and radiation therapy,36 are potentially deleterious to IBD patients or pose significant side effects, which have limited exploration of antiangiogenic strategies for chronic inflammation at the present time.37

Over the past decade, antiangiogenic therapy has become a reality in the treatment of metastatic tumors. The emergence of antiangiogenic therapy in cancer treatment is a direct legacy of the pioneering investigation of Judah Folkman, where anti-VEGF therapy with the compound bevacizumab, received FDA approval for the treatment of metastatic colorectal adenocarcinoma.38 Novel compounds targeting blood vessel growth are currently undergoing investigation. The natural compound curcumin, a component Ayurvedic medicine for centuries and a component of the spice turmeric, has antiangiogenic potential, demonstrating significant ability to inhibit the growth of HIMEC in vitro.39 This mechanistic insight into curcumin's therapeutic potential is intriguing; this compound has demonstrated efficacy in maintenance of UC remission in a multicenter, randomized, controlled trial.40

One of the important issues that needs to be considered regarding the evaluation of antiangiogenic therapy in the treatment of Crohn's disease and ulcerative colitis is the design of appropriate clinical trials. If tissue remodeling and blood vessel growth are slow and gradual processes, then inhibiting blood vessel growth and reversing pathologic angiogenesis will likewise represent a slow process. Trial endpoints evaluating long-term outcome and reversal of structural remodeling of the chronically inflamed bowel may need to emerge to assess these agents and their potential efficacy.

In summary, our understanding of the contribution of the gut microvasculature to the process of chronic inflammation in IBD continues to expand. The gut microvascular endothelium, once considered an inert tube in which leukocytes would travel into the intestine, is now gaining importance as a critical cellular component that serves to initiate and perpetuate inflammation. Leukocyte recruitment through endothelial interaction has emerged as a therapeutic reality in the treatment of Crohn's disease and is undergoing evaluation for the treatment of UC. The 2 papers by Chidlow et al30 and Scaldaferri et al26 in this issue of Gastroenterology highlight an additional component of the vascular biology of IBD, angiogenesis. These studies demonstrating the therapeutic potential of antiangiogenic strategies provide further evidence for new treatment strategies that target neovascularization and tissue remodeling in hopes of maximizing treatment responses in our patients with refractory IBD.

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PII: S0016-5085(08)02208-7

doi:10.1053/j.gastro.2008.12.029

Refers to article:

  • Linking Article with CGHEditorial Accompanies this ArticleAdditional Online Content Available Endothelial Caveolin-1 Regulates Pathologic Angiogenesis in a Mouse Model of Colitis , 11 November 2008

    John H. Chidlow, Joshua J.M. Greer, Christoph Anthoni, Pascal Bernatchez, Carlos Fernadez–Hernando, Megan Bruce, Maisoun Abdelbaqi, Deepti Shukla, D. Neil Granger, William C. Sessa, Christopher G. Kevil
    Gastroenterology February 2009 (Vol. 136, Issue 2, Pages 575-584.e2)

  • Editorial Accompanies this ArticleLinking Article with CGHAdditional Online Content Available VEGF-A Links Angiogenesis and Inflammation in Inflammatory Bowel Disease Pathogenesis , 06 October 2008

    Franco Scaldaferri, Stefania Vetrano, Miquel Sans, Vincenzo Arena, Giuseppe Straface, Egidio Stigliano, Alessandro Repici, Andreas Sturm, Alberto Malesci, Julian Panes, Seppo Yla–Herttuala, Claudio Fiocchi, Silvio Danese
    Gastroenterology February 2009 (Vol. 136, Issue 2, Pages 585-595.e5)

Gastroenterology
Volume 136, Issue 2 , Pages 400-403, February 2009

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