Angiogenesis as a novel component of inflammatory bowel disease pathogenesis.
OBJECTIVE
Angiogenesis is a critical component of neoplastic and chronic inflammatory disorders, but whether angiogenesis also occurs in inflammatory bowel disease (IBD) has yet to be established. We assessed mucosal vascularization, expression of endothelial alphaVbeta3 integrin, angiogenic factors, and their bioactivity in Crohn's disease (CD) and ulcerative colitis (UC) mucosa.


METHODS
Mucosal endothelium was immunostained for CD31 and factor VIII and quantified by digital morphometry. alphaVbeta3 expression was studied in vivo by confocal microscopy and in vitro by flow cytometric analysis of human intestinal microvascular endothelial cells (HIMECs). Vascular endothelial growth factor (VEGF), interleukin (IL)-8, and bFGF levels were measured in mucosal extracts and cells and angiogenic bioactivity shown by induction of HIMEC migration and the corneal and chorioallantoic membrane angiogenesis assays.


RESULTS
Microvessel density was increased in IBD mucosa. Endothelial alphaVbeta3 was strongly expressed in IBD but only sporadically in normal mucosa and was up-regulated in HIMECs by VEGF, tumor necrosis factor alpha, and bFGF. IBD mucosal extracts induced a significantly higher degree of HIMEC migration than control mucosa, and this response was mostly dependent on IL-8 and less on basic fibroblast growth factor or vascular endothelial growth factor. Compared with normal mucosa, IBD mucosal extracts induced a potent angiogenic response in both the corneal and chorioallantoic membrane assays.


CONCLUSIONS
These results provide morphological, phenotypic and functional evidence of potent angiogenic activity in both CD and UC mucosa, indicating that the local microvasculature undergoes an intense process of inflammation-dependent angiogenesis. Thus, angiogenesis appears to be an integral component of IBD pathogenesis, providing the practical and conceptual framework for anti-angiogenic therapies in IBD.
Danese
Silvio
S
Division of Gastroenterology, Istituto Clinico Humanitas, IRCCS in Gastroenterology, Rozzano, Milan, Italy. sdanese@hotmail.com
Sans
Miquel
M
de la Motte
Carol
C
Graziani
Cristina
C
West
Gail
G
Phillips
Manijeh H
MH
Pola
Roberto
R
Rutella
Sergio
S
Willis
Joe
J
Gasbarrini
Antonio
A
Fiocchi
Claudio
C
D001707:Biopsy, Needle; D016022:Case-Control Studies; D002478:Cells, Cultured; D002633:Chemotaxis; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000032:analysis*; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000473:pathology*; D016023:Integrins / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D007413:Intestinal Mucosa / Q000098:blood supply / Q000166:cytology* / Q000473:pathology; D008297:Male; D008833:Microcirculation / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000473:pathology*; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D018836:Inflammation Mediators; D016023:Integrins; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2