title: Liver growth factor treatment restores cell-extracellular matrix balance in resistance arteries and improves left ventricular hypertrophy in SHR.
abstract: Liver growth factor (LGF) is an endogenous albumin-bilirubin complex with antihypertensive effects in spontaneously hypertensive rats (SHR). We assessed the actions of LGF treatment on SHR mesenteric resistance and intramyocardial arteries (MRA and IMA, respectively), heart, and vascular smooth muscle cells (VSMC). SHR and Wistar-Kyoto (WKY) rats treated with vehicle or LGF (4.5 μg LGF/rat, 4 ip injections over 12 days) were used. Intra-arterial blood pressure was measured in anesthetized rats. The heart was weighted and paraffin-embedded. Proliferation, ploidy, and fibronectin deposition were studied in carotid artery-derived VSMC by immunocytochemistry. In MRA, we assessed: 1) geometry and mechanics by pressure myography; 2) function by wire myography; 3) collagen by sirius red staining and polarized light microscopy, and 4) elastin, cell density, nitric oxide (NO), and superoxide anion by confocal microscopy. Heart sections were used to assess cell density and collagen content in IMA. Left ventricular hypertrophy (LVH) regression was assessed by echocardiography. LGF reduced blood pressure only in SHR. LGF in vitro or as treatment normalized the alterations in proliferation and fibronectin in SHR-derived VSMC with no effect on WKY cells. In MRA, LGF treatment normalized collagen, elastin, and VSMC content and passive mechanical properties. In addition, it improved NO availability through reduction of superoxide anion. In IMA, LGF treatment normalized perivascular collagen and VSMC density, improving the wall-to-lumen ratio. Paired experiments demonstrated a partial regression of SHR LVH by LGF treatment. The effective cardiovascular antifibrotic and regenerative actions of LGF support its potential in the treatment of hypertension and its complications.
authors.affiliation: Facultad de Medicina, Departamentos de Fisiologia, Universidad Autonoma de Madrid, Madrid Spain.
authors.forename: M Victoria
authors.initials: MV
authors.lastname: Conde
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Gonzalez
authors.forename: Begoña
authors.initials: B
authors.lastname: Quintana-Villamandos
authors.forename: Fatima
authors.initials: F
authors.lastname: Abderrahim
authors.forename: Ana M
authors.initials: AM
authors.lastname: Briones
authors.forename: Luis
authors.initials: L
authors.lastname: Condezo-Hoyos
authors.forename: Javier
authors.initials: J
authors.lastname: Regadera
authors.forename: Cristina
authors.initials: C
authors.lastname: Susin
authors.forename: Jose J
authors.initials: JJ
authors.lastname: Gomez de Diego
authors.forename: Emilio
authors.initials: E
authors.lastname: Delgado-Baeza
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Diaz-Gil
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Arribas
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001663:Bilirubin / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004549:Elastin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018613:Microscopy, Confocal; D008859:Microscopy, Polarization; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D009213:Myography; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012709:Serum Albumin / Q000008:administration & dosage*; D000075462:Serum Albumin, Human; D013481:Superoxides / Q000378:metabolism; D014463:Ultrasonography; D014655:Vascular Resistance / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D005353:Fibronectins; D012709:Serum Albumin; D014665:Vasodilator Agents; C053498:albumin-bilirubin complex; D013481:Superoxides; D009569:Nitric Oxide; D003094:Collagen; D004549:Elastin; D019001:Nitric Oxide Synthase; D001663:Bilirubin; D000075462:Serum Albumin, Human