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This Article Full Text Full Text (PDF) Supplemental data All Versions of this Article: 583/2/753    most recent jphysiol.2007.136325v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Milkiewicz, M. Articles by Haas, T. L. Search for Related Content PubMed PubMed Citation Articles by Milkiewicz, M. Articles by Haas, T. L. Related Collections Skeletal Muscle and Exercise

¹ School of Kinesiology and Health Sciences, York University, Toronto, ON, Canada
² Department of Laboratory Diagnostics and Molecular Medicine, Pomeranian Medical University, Szczecin, Poland

Angiogenesis, which is essential for the physiological adaptation of skeletal muscle to exercise, occurs in response to the mechanical forces of elevated capillary shear stress and cell stretch. Increased production of VEGF is a characteristic of endothelial cells undergoing either stretch- or shear-stress-induced angiogenesis. Because VEGF production is regulated by hypoxia inducible factors (HIFs), we examined whether HIFs play a significant role in the angiogenic process initiated by these mechanical forces. Rat extensor digitorum longus (EDL) muscles were overloaded to induce stretch, or exposed to the dilator prazosin to elevate capillary shear stress, and capillaries from these muscles were isolated by laser capture microdissection for RNA analysis. HIF-1 and HIF-2 transcript levels increased after 4 and 7 days of stretch, whereas a transient early induction of HIF-1 and HIF-2 transcripts was detected in capillaries from prazosin-treated muscles. Skeletal muscle microvascular endothelial cells exposed to 10% stretch in vitro showed an elevation in HIF-1 and HIF-2 mRNA, which was preceded by increases in HIF-binding activity. Conversely, HIF-1 and HIF-2 mRNA were reduced significantly, and HIF- proteins were undetectable, after 24 h exposure to elevated shear stress (16 dyn cm^–2 (16 x10^–5 N cm^–2). Given the disparate regulation of HIFs in response to these mechanical stimuli, we tested the requirement of HIF- proteins in stretch- and shear-stress-induced angiogenesis by impeding HIF accumulation through use of the geldanamycin derivative 17-DMAG. Treatment with 17-DMAG significantly impaired stretch-induced, but not shear-stress-induced, angiogenesis. Together, these results illustrate that activation of HIF-1 and HIF-2 contributes significantly to stretch- but not to shear-stress-induced capillary growth.

(Received 11 May 2007; accepted after revision 5 July 2007; first published online 12 July 2007)
Corresponding author T. L. Haas: School of Kinesiology and Health Sciences, Farquharson Building, Room 341, York University, 4700 Keele St, Toronto, Ontario, Canada M3J 1P3. Email: thaas{at}yorku.ca