Liver growth factor treatment restores cell-extracellular matrix balance in resistance arteries and improves left ventricular hypertrophy in SHR

Abstract

Conde MV, Gonzalez MC, Quintana-Villamandos B, Abderrahim F, Briones AM, Condezo-Hoyos L, Regadera J, Susin C, de Diego JJ, Delgado-Baeza E, Diaz-Gil JJ, Arribas SM. Liver growth factor treatment restores cell-extracellular matrix balance in resistance arteries and improves left ventricular hypertrophy in SHR. Am J Physiol Heart Circ Physiol 301: H1153-H1165, 2011. First published June 3, 2011 doi:10.1152/ajpheart.00886.2010.-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 g LGF/rat, 4 ip injections over 12 days) were used. Intra-arterial blood pressure was measured in anesthetized rats. The heart was weighted and paraffinembedded. 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. intramyocardial arteries; mesenteric resistance arteries; nitric oxide; vascular remodeling; left ventricular hypertrophy LIVER GROWTH FACTOR (LGF) was first described as an endogenous factor with mitogenic properties in liver (21).LGF is not detected in physiological conditions, but it increases in plasma in situations of hepato-biliary disorders, both in humans and rats (21,24). The chemical analysis of LGF obtained from human and rat plasma has revealed that it is a covalently bound albumin-bilirubin complex (24,25). The regenerative effects of LGF, initially described in hepato-biliary disorders (22,23,26), have been recently extended to other diseases, such as Parkinson's disease (35, 52), testicular degeneration (51), and pulmonary fibrosis (47).LGF treatment also has cardiovascular effects as previously shown in rodent models of hype...

Fetal undernutrition is associated with perinatal sex-dependent alterations in oxidative status

“…Hypertension is associated with cardiovascular fibrosis, remodeling and endothelial dysfunction, alterations where oxidative stress plays a key role [37][38][39]. Similar cardiovascular alterations have been found in adult IUGR rats [40][41][42] and therefore oxidative stress has been proposed as a possible mechanism implicated in fetal programming of hypertension [7,43].…”

Liver growth factor treatment reverses vascular and plasmatic oxidative stress in spontaneously hypertensive rats

“…We have previously published that 12-day LGF treatment of SHR reduces blood pressure and LVH, markedly improving vascular fibrosis and vasodilatation [28,29]. Since all these alterations in the SHR model are linked to oxidative stress [44,45], we hypothesize that LGF might be able to exert its regenerative actions, at least in part, through an antioxidant mechanism.…”

“…LGF is an endogenous factor which is not detected in physiological conditions but it increases its concentration in plasma in hepato-biliary disorders, both in humans and rats [26,27]. We have previously demonstrated that short treatment (12 days) with LGF of spontaneously hypertensive rats (SHRs) significantly reduces blood pressure, vascular fibrosis, endothelial dysfunction and left-ventricular hypertrophy [28,29].…”

Arterial stiffness is associated with adipokine dysregulation in non-hypertensive obese mice

“…Fibrillar type I/III collagens are the most abundant in vascular walls 49 and they play an important contribution to the rigidity of the arterial wall of resistance arteries in hypertension 6,9,31,50 . In this study, MA from HFD show augmented content of type I collagen, which comprises 60% of the vascular wall collagens 51 , without changes in type III collagen.…”