Angiopoietin-1 prevents severe bleeding complications induced by heparin-like drugs and fibroblast growth factor-2 in mice.
Critically ill children can develop bleeding complications when treated with heparin-like drugs. These events are usually attributed to the anticoagulant activity of these drugs. However, previous studies showed that fibroblast growth factor-2 (FGF-2), a heparin-binding growth factor released in the circulation of these patients, could precipitate intestinal hemorrhages in mice treated with the heparin-like drug pentosan polysulfate (PPS). Yet very little is known about how FGF-2 induces bleeding complications in combination with heparin-like drugs. Here, we examined the mechanisms by which circulating FGF-2 induces intestinal hemorrhages in mice treated with PPS. We used a well-characterized mouse model of intestinal hemorrhages induced by FGF-2 plus PPS. Adult FVB/N mice were infected with adenovirus carrying Lac-Z or a secreted form of recombinant human FGF-2, and injected with PPS, at doses that do not induce bleeding complications per se. Mice treated with FGF-2 in combination with PPS developed an intestinal inflammatory reaction that increased the permeability and disrupted the integrity of submucosal intestinal vessels. These changes, together with the anticoagulant activity of PPS, induced lethal hemorrhages. Moreover, a genetically modified form of the endothelial ligand angiopoietin-1 (Ang-1*), which has powerful antipermeability and anti-inflammatory activity, prevented the lethal bleeding complications without correcting the anticoagulant status of these mice. These findings define new mechanisms through which FGF-2 and Ang-1* modulate the outcome of intestinal bleeding complications induced by PPS in mice and may have wider clinical implications for critically ill children treated with heparin-like drugs.
Center for Genetic Medicine Research, Children's National Medical Center, Washington, District of Columbia;
Marina
M
Jerebtsova
Center for Genetic Medicine Research, Children's National Medical Center, Washington, District of Columbia;
Jharna R
JR
Das
Center for Genetic Medicine Research, Children's National Medical Center, Washington, District of Columbia;
Pingtao
P
Tang
Division of Laboratory Medicine, Children's National Medical Center, Washington, District of Columbia; Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia.
Edward
E
Wong
Center for Genetic Medicine Research, Children's National Medical Center, Washington, District of Columbia; Division of Nephrology, Children's National Medical Center, Washington, District of Columbia; and Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia Pray@cnmc.org.
Patricio E
PE
Ray
D000256:Adenoviridae / Q000235:genetics; D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001777:Blood Coagulation; D002199:Capillary Permeability; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D007421:Intestine, Small / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D010426:Pentosan Sulfuric Polyester
D042683:Angiopoietin-1; D018836:Inflammation Mediators; D016222:Fibroblast Growth Factor 2; D010426:Pentosan Sulfuric Polyester; D020782:Matrix Metalloproteinases
angiopoietin-1; fibroblast growth factor-2; heparin-like drugs; intestinal bleeding; vascular permeability