title: Placental growth factor regulates cardiac adaptation and hypertrophy through a paracrine mechanism.
abstract: BACKGROUND
  Paracrine growth factor-mediated crosstalk between cardiac myocytes and nonmyocytes in the heart is critical for programming adaptive cardiac hypertrophy in which myocyte size, capillary density, and the extracellular matrix function coordinately.
  
  
  OBJECTIVE
  To examine the role that placental growth factor (PGF) plays in the heart as a paracrine regulator of cardiac adaptation to stress stimulation.
  
  
  RESULTS
  PGF is induced in the heart after pressure-overload stimulation, where it is expressed in both myocytes and nonmyocytes. We generated cardiac-specific and adult inducible PGF-overexpressing transgenic mice and analyzed Pgf(-/-) mice to examine the role that this factor plays in cardiac disease and paracrine signaling. Although PGF transgenic mice did not have a baseline phenotype or a change in capillary density, they did exhibit a greater cardiac hypertrophic response, a greater increase in capillary density, and increased fibroblast content in the heart in response to pressure-overload stimulation. PGF transgenic mice showed a more adaptive type of cardiac growth that was protective against signs of failure with pressure overload and neuroendocrine stimulation. Antithetically, Pgf(-/-) mice rapidly died of heart failure within 1 week of pressure overload, they showed an inability to upregulate angiogenesis, and they showed significantly less fibroblast activity in the heart. Mechanistically, we show that PGF does not have a direct effect on cardiomyocytes but works through endothelial cells and fibroblasts by inducing capillary growth and fibroblast proliferation, which secondarily support greater cardiac hypertrophy through intermediate paracrine growth factors such as interleukin-6.
  
  
  CONCLUSIONS
  PGF is a secreted factor that supports hypertrophy and cardiac function during pressure overload by affecting endothelial cells and fibroblasts that in turn stimulate and support the myocytes through additional paracrine factors.
authors.affiliation: Howard Hughes Medical Institute, Cincinnati Children's Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Accornero
authors.forename: Jop H
authors.initials: JH
authors.lastname: van Berlo
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Benard
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology*; D003326:Coronary Circulation / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000502:physiology; D019899:Paracrine Communication / Q000502:physiology*; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology
chemical_list: C000608037:Pgf protein, mouse; D011257:Pregnancy Proteins; D000072483:Placenta Growth Factor