Negative Regulators of Angiogenesis in Inflammatory Bowel Disease: Thrombospondin in the Spotlight

Both ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel diseases, are recognized, at the moment, as perplexing and challenging clinical entities, in which several molecules and cell types are implicated. Recent molecular evidence proposes the intestinal microvascular remodelling or angiogenesis, as a phenomenon implicated in the pathogenesis of these chronic inflammatory disorders, together with other proposed theories involved in the pathogenesis of inflammatory bowel diseases, such as genetic, microbacterial and immune factors. Intestinal damage is followed by a physiological angiogenesis, but the abnormal expression of pro- and anti-angiogenic molecules and the changes of vascular cell types could reflect a pathological vascular remodelling. Thus, the inflammation may be favoured and maintained by a pathological angiogenesis. A better understanding of the angiogenic process may facilitate the design of more effective therapies for chronic intestinal inflammation.

Multiple Pathogenic Roles of Microvasculature in Inflammatory Bowel Disease: A Jack of All Trades

Unique Role of Junctional Adhesion Molecule-A in Maintaining Mucosal Homeostasis in Inflammatory Bowel Disease

Several studies have shown alterations in vascular anatomy and physiology in inflammatory bowel disease (IBD). These findings, together with the observed upregulation of the mediators of angiogenesis in IBD patients, suggest that angiogenesis possibly contributes to the initiation and perpetuation of IBD. There is considerable evidence of an interrelationship between the mechanisms of angiogenesis and chronic inflammation in IBD. The increased expression of endothelial junction adhesion molecules found in IBD patients indicates the presence of active angiogenesis. Evidence that angiogenesis is involved in IBD was also obtained from animal models of colitis, most notably from studies of angiogenesis inhibition. Serum levels of vascular endothelial growth factor (VEGF) correlate with disease activity in human IBD and fall with the use of steroids, thalidomide, or infliximab. Pharmacological inhibition of angiogenesis, therefore, has the potential to be a therapeutic strategy in IBD. This review outlines the evidence that the rate of angiogenesis is increased in the inflamed intestine in IBD and proposes lines for future research in this field.

Cutaneous infantile hemangioma progresses through proliferation and involution phases. Since treatment with interferon, a negative regulator of angiogenesis, accelerates the involution phase, we hypothesized that cutaneous infantile hemangioma is associated with an imbalance between endogenous positive and negative regulators of angiogenesis. We examined 30 specimens of cutaneous hemangioma [proliferative phase (n=15), involuting phase (n=8), and involuted phase (n=7)] and control human skin (n=17), fixed in formalin and embedded in paraffin. Routine histology, immunohistochemistry, and an mRNA in situ hybridization technique were used to measure expression of the positive angiogenic molecules basic fibroblast growth factor (bFGF) and vascular endothelial growth factor/vascular permeability factor (VEGF/VPF), and an endogenous inhibitor of angiogenesis, interferon-beta (IFN-beta). Proliferative phase hemangiomas expressed high levels of bFGF and VEGF/VPF but not IFN-beta (mRNA and protein). The epidermis directly overlying proliferating hemangiomas was hyperplastic, contained numerous dividing cells, and expressed bFGF and VEGF/VPF but not IFN-beta. Epidermis from normal individuals and epidermis directly overlying involuted tumors or at sites distant to the proliferating hemangioma was not hyperplastic and expressed normal levels of bFGF, VEGF/VPF, and IFN-beta. These data suggest that the proliferation of cutaneous hemangiomas and adjacent epidermis is associated with an imbalance between positive and negative angiogenic factors expressed by the neoplasm and adjacent normal tissue.

SummaryInterleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23-independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3+ cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.

Mast cells and eosinophils: A novel link between inflammation and angiogenesis in allergic diseases

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic intestinal inflammation and impaired epithelial barrier function. Emerging evidence highlights the critical role of vascular remodeling and angiogenesis in IBD pathogenesis. This review explores the intricate relationship between blood vessels and the intestinal epithelial barrier, emphasizing how aberrant vascularization contributes to barrier dysfunction and disease progression. In IBD, excessive angiogenesis is driven by hypoxia, immune cell infiltration, and pro-inflammatory cytokines, further perpetuating inflammation and tissue damage. Key angiogenic factors, such as vascular endothelial growth factor (VEGF), angiopoietins, and platelet-derived growth factor (PDGF), are upregulated in IBD, promoting pathological vessel formation. These newly formed vessels are often immature and hyperpermeable, exacerbating leukocyte recruitment and inflammatory responses. Given the pivotal role of angiogenesis in IBD, anti-angiogenic therapies have emerged as a potential therapeutic strategy. Preclinical and clinical studies targeting VEGF and other angiogenic pathways have shown promise in reducing inflammation and promoting mucosal healing. This review summarizes current knowledge on vascular-epithelial interactions in IBD, the mechanisms driving pathological angiogenesis, and the therapeutic potential of anti-angiogenic approaches, providing insights for future research and treatment development.

Background and aims Inflammatory bowel disease (IBD) cause chronic relapsing-remitting inflammatory flares in the gastrointestinal tract, resulting in abdominal pain, diarrhea, and gut dysmotility in non-destructive collagenous and lymphocytic microscopic colitis. In addition, classic IBDs Crohn´s disease and ulcerative colitis cause bloody diarrhea and extraintestinal symptoms. Non-destructive IBDs seem to restrain an overt immune response that will damage the tissue and impair wound healing. Thus, I will work under the premise that non-destructive IBDs are undeveloped forms of classic IBDs. Methods First, I aim to deeply characterize and compare immune cells and their activation levels in all forms of IBD using “immunomics” (spectral/computational cytometry) and validate my previous finding of two subtypes of lymphocytic colitis. To identify the microbiota that adheres to intestinal epithelial cell (IEC) and therefore alter permeability, and induce collagen deposition, I will coculture IEC and fibroblasts in organ-on-a-chip platforms to mimic gut conditions, including microflow shear stress. I will stimulate chips with patient-derived microbiota-containing luminal content or homogenized biopsies and resections from collagenous colitis (characterized by pathogenic collagen position) and intestinal fibrosis (a major, irreversible IBD complication that increases mortality), respectively, and study using different sequencing techniques. Of note, collagenous colitis could resemble early stages of intestinal fibrosis. My third objective aims to test my previous observation that regulatory B-cells in collagenous colitis might be responsible of restricting overt inflammation. Anticipated impact I will adapt spectral cytometry panels to characterize the state of mucosal B- and plasma cells. The support of my host, the well-established IBD immunologist Assoc. Prof. David Bernardo at the Institute of Biomedicine and Molecular Genetics (Valladolid, Spain, h-index=33) and me as coordinator of the biobank for the European Microscopic Colitis Group, ensure the feasibility to complete my ambitious research agenda and make a great impact on IBD field to discover disease-specific biomarkers, pathomechanisms, and new druggable targets.

The effect of methylprednisolone and cyclosporine A in a murine model of intestinal inflammation

Role of Blood- and Tissue-Associated Inducible Nitric-Oxide Synthase in Colonic Inflammation

Inflammatory bowel disease (IBD), the precise etiology of which remains unknown, is comprised of two forms of chronic intestinal inflammation; ulcerative colitis (UC) and Crohn's disease (CD). Recent evidence increasingly suggests that IBD is the result of dysfunctional immunoregulation manifested by inappropriate production of mucosal cytokines. An abnormal microcirculatory system has also been implicated in its pathogenesis. To elucidate the mechanism of ischemic change in IBD, we assesse serum concentration levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF), and plasma level of endothelin-1 (ET-1). We also investigated the expression of VEGF, b-FGF, and transforming growth factor-beta1,2,3 (TGF-beta1,2,3) in tissue by immunostaining. Blood samples were obtained from 11 patients with UC, 11 patients with CD, and 10 patients as controls. Paraffin-embedded samples were used for an immunohistochemical study. The concentration levels (in picograms per milliliter) were as follows: for ET-1, UC: 127+/-47.0, CD: 167.3+/-35.1, and controls (asthma: 38.5+/-23.8, p < 0.01; diverticulitis: 40.5+/-25.6, p < 0.01), for b-FGF, UC: 9.2+/-1.9, CD: 9.1+/-1.5, and controls (asthma: 5.0+/-0, p < 0.01; diverticulitis: 5.0+/-0, p < 0.01), for VEGF, UC: 659.8+/-181.0, CD: 740.0+/-182.3, and controls (asthma: 193.7+/-58.7, p < 0.01; diverticulitis: 199.6+/-59.7, p < 0.01). The levels of VEGF and b-FGF were significantly higher in active IBD than those in the controls. There was a significant positive correlation among the serum levels of VEGF and b-FGF and the plasma level of ET-1; that is, elevated VEGF, b-FGF, and ET-1 levels correlated well with each other. Immunohistochemical studies showed increased venula in the submucosa and lamina propria. Overexpression of VEGF and b-FGF in endothelial cells was revealed and TGF-beta2 and TGF-beta3 were found in inflammatory cells of active IBD, but no change was observed around the vessels in the controls. It is suggested that the reciprocal reaction of these cytokines may contribute to angiogenesis in IBD b inducing intestinal ischemia through vasoconstriction.

VEGF, basic-FGF, and TGF-β in Crohn’s disease and ulcerative colitis: a novel mechanism of chronic intestinal inflammation

To investigate whether narrow band imaging (NBI) is a useful tool for the in vivo detection of angiogenesis in inflammatory bowel disease (IBD) patients. Conventional and NBI colonoscopy was performed in 14 patients with colonic inflammation (8 ulcerative colitis and 6 Crohn's disease). Biopsy samples were taken and CD31 expression was assayed immunohistochemically; microvascular density was assessed by vessel count. In areas that were endoscopically normal but positive on NBI, there was a significant (P < 0.05) increase in angiogenesis (12 +/- 1 vessels/field vs 18 +/- 2 vessels/field) compared with areas negative on NBI. In addition, in areas that were inflamed on white light endoscopy and positive on NBI, there was a significant (P < 0.01) increase in vessel density (24 +/- 7 vessels/field) compared with NBI-negative areas. NBI may allow in vivo imaging of intestinal angiogenesis in IBD patients.

An Apple a Day Keeps the Doctor Away: The Effect of a Low-Fat, High-Fiber Diet on Quality of Life, Inflammation, and Dysbiosis in Patients With Ulcerative Colitis