title: Muscle-derived vascular endothelial growth factor regulates microvascular remodelling in response to increased shear stress in mice.
abstract: OBJECTIVE
  The source of vascular endothelial growth factor-A (VEGF-A) may influence vascular function. Exercise-induced vascular growth has been attributed to elevated metabolic demand and to increased blood flow, involving the production of VEGF-A by skeletal muscle and by endothelial cells respectively. We hypothesized that muscle-derived VEGF-A is not required for vascular adaptations to blood flow in skeletal muscle, as this remodelling stimulus originates within the capillary.
  
  
  METHODS
  Myocyte-specific VEGF-A (mVEGF(-/-) ) deleted mice were treated for 7-21 days with the vasodilator prazosin to produce a sustained increase in skeletal muscle blood flow.
  
  
  RESULTS
  Capillary number increased in the extensor digitorum longus (EDL) muscle in response to prazosin in wild type but not mVEGF(-/-) mice. Prazosin increased the number of smooth muscle actin-positive blood vessels in the EDL of wild-type but not mVEGF(-/-) mice. The average size of smooth muscle actin-positive blood vessels also was smaller in knockout mice after prazosin treatment. In response to prazosin treatment, VEGF-A mRNA was elevated within the EDL of wild-type but not mVEGF(-/-) mice. Ex vivo incubation of wild-type EDL with a nitric oxide donor increased VEGF-A mRNA. Likewise, we demonstrated that nitric oxide donor treatment of cultured myoblasts stimulated an increase in VEGF-A mRNA and protein.
  
  
  CONCLUSIONS
  These results suggest a link through which flow-mediated endothelial-derived signals may promote myocyte production of VEGF-A. In turn, myocyte-derived VEGF-A is required for appropriate flow-mediated microvascular remodelling. This highlights the importance of the local environment and paracrine interactions in the regulation of tissue perfusion.
authors: School of Kinesiology and Health Science, Angiogenesis Research Group, York University, Toronto, ON, Canada.
authors: C
authors: C
authors: Uchida
authors: School of Kinesiology and Health Science, Angiogenesis Research Group, York University, Toronto, ON, Canada.
authors: E
authors: E
authors: Nwadozi
authors: School of Kinesiology and Health Science, Angiogenesis Research Group, York University, Toronto, ON, Canada.
authors: A
authors: A
authors: Hasanee
authors: Division of Exercise Physiology & Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV, USA.
authors: S
authors: S
authors: Olenich
authors: Division of Exercise Physiology & Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, WV, USA.
authors: I M
authors: IM
authors: Olfert
authors: School of Kinesiology and Health Science, Angiogenesis Research Group, York University, Toronto, ON, Canada.
authors: T L
authors: TL
authors: Haas
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology; D002196:Capillaries / Q000502:physiology*; D005260:Female; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000502:physiology*; D033081:Shear Strength / Q000502:physiology; D013314:Stress, Mechanical; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D066253:Vascular Remodeling / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A
keywords: angiogenesis; nitric oxide; skeletal muscle