title: Novel role for endogenous hepatocyte growth factor in the pathogenesis of intracranial aneurysms.
abstract: Inflammation plays a key role in formation and rupture of intracranial aneurysms. Because hepatocyte growth factor (HGF) protects against vascular inflammation, we sought to assess the role of endogenous HGF in the pathogenesis of intracranial aneurysms. Circulating HGF concentrations in blood samples drawn from the lumen of human intracranial aneurysms or femoral arteries were compared in 16 patients. Tissue from superficial temporal arteries and ruptured or unruptured intracranial aneurysms collected from patients undergoing clipping (n=10) were immunostained with antibodies to HGF and its receptor c-Met. Intracranial aneurysms were induced in mice treated with PF-04217903 (a c-Met antagonist) or vehicle. Expression of inflammatory molecules was also measured in cultured human endothelial, smooth muscle cells and monocytes treated with lipopolysaccharides in presence or absence of HGF and PF-04217903. We found that HGF concentrations were significantly higher in blood collected from human intracranial aneurysms (1076±656 pg/mL) than in femoral arteries (196±436 pg/mL; P<0.001). HGF and c-Met were detected by immunostaining in superficial temporal arteries and in both ruptured and unruptured human intracranial aneurysms. A c-Met antagonist did not alter the formation of intracranial aneurysms (P>0.05), but significantly increased the prevalence of subarachnoid hemorrhage and decreased survival in mice (P<0.05). HGF attenuated expression of vascular cell adhesion molecule-1 (P<0.05) and E-Selectin (P<0.05) in human aortic endothelial cells. In conclusion, plasma HGF concentrations are elevated in intracranial aneurysms. HGF and c-Met are expressed in superficial temporal arteries and in intracranial aneurysms. HGF signaling through c-Met may decrease inflammation in endothelial cells and protect against intracranial aneurysm rupture.
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Peña-Silva
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Nohra
authors.initials: N
authors.lastname: Chalouhi
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Lauren
authors.initials: L
authors.lastname: Wegman-Points
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ali
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Ian
authors.initials: I
authors.lastname: Mitchell
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Gary L
authors.initials: GL
authors.lastname: Pierce
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Yi
authors.initials: Y
authors.lastname: Chu
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Zuhair K
authors.initials: ZK
authors.lastname: Ballas
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.).
authors.forename: Donald
authors.initials: D
authors.lastname: Heistad
authors.affiliation: From the Departments of Pharmacology and Neurosurgery, Medical School, Universidad de los Andes, Bogotá, Colombia (R.A.P.-S.); Department of Neurosurgery, Thomas Jefferson University School of Medicine, Philadelphia, PA (N.C.); Department of Health and Human Physiology, University of Iowa, Iowa City (L.W.-P., G.L.P.); Departments of Neurosurgery (M.A., I.M., Y.C., D. Hasan) and Medicine (Y.C., Z.K.B., D. Heistad), University of Iowa Carver College of Medicine, Iowa City; and Department of Medicine, VA Medical Center, Iowa City, IA (Z.K.B.). david-hasan@uiowa.edu.
authors.forename: David
authors.initials: D
authors.lastname: Hasan
mesh_terms: D000328:Adult; D000368:Aged; D017542:Aneurysm, Ruptured / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D019040:E-Selectin / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D002532:Intracranial Aneurysm / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C558663:2-(4-(3-quinolin-6-ylmethyl-3H-(1,2,3)triazolo(4,5-b)pyrazin-5-yl)pyrazol-1-yl)ethanol; D019040:E-Selectin; C066855:HGF protein, human; C553307:HGF protein, mouse; D011719:Pyrazines; D014230:Triazoles; D019010:Vascular Cell Adhesion Molecule-1; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
keywords: C-met; E-selectin; VCAM-1; hepatocyte growth factor; inflammation; intracranial aneurysm; subarachnoid hemorrhage