title: Prazosin Can Prevent Glucocorticoid Mediated Capillary Rarefaction.
abstract: Glucocorticoids (GC) elicit skeletal muscle capillary rarefaction, which can subsequently impair blood distribution and muscle function; however, the mechanisms have not been established. We hypothesized that CORT would inhibit endothelial cell survival signals but that treatment with the alpha-1 adrenergic receptor inhibitor prazosin, which leads to angiogenesis in skeletal muscle of healthy rats, would reverse these effects and induce angiogenesis within the skeletal muscle of corticosterone (CORT)-treated rats. Male Sprague Dawley rats were implanted subcutaneously with CORT pellets (400 mg/rat), with or without concurrent prazosin treatment (50mg/L in drinking water), for 1 or 2 weeks. Skeletal muscle capillary rarefaction, as indicated by a significant reduction in capillary-to-fiber ratio (C:F), occurred after 2 weeks of CORT treatment. Concurrent prazosin administration prevented this capillary rarefaction in CORT-treated animals but did not induce angiogenesis or arteriogenesis as was observed with prazosin treatment in control rats. CORT treatment reduced the mRNA level of Angiopoietin-1 (Ang-1), which was partially offset in the muscles of rats that received 2 weeks of co-treatment with prazosin. In 2W CORT animals, prazosin treatment elicited a significant increase in vascular endothelial growth factor-A (VEGF-A) mRNA and protein. Conversely prazosin did not rescue CORT-induced reductions in transforming growth factor beta-1 (TGFβ1 and matrix metalloproteinase-2 (MMP-2) mRNA. To determine if CORT impaired shear stress dependent signaling, cultured rat skeletal muscle endothelial cells were pre-treated with CORT (600nM) for 48 hours, then exposed to 15 dynes/cm2 shear stress or maintained with no flow. CORT blunted the shear stress-induced increase in pSer473 Akt, while pThr308 Akt, ERK1/2 and p38 phosphorylation and nitric oxide (NO) production were unaffected. This study demonstrates that GC-mediated capillary rarefaction is associated with a reduction in Ang-1 mRNA within the skeletal muscle microenvironment and that concurrent prazosin treatment effectively increases VEGF-A levels and prevents capillary loss.
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Canada.
authors.forename: Erin R
authors.initials: ER
authors.lastname: Mandel
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Canada.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Dunford
authors.affiliation: Department of Biology, York University, Toronto, Canada.
authors.forename: Anastassia
authors.initials: A
authors.lastname: Trifonova
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Canada.
authors.forename: Ghoncheh
authors.initials: G
authors.lastname: Abdifarkosh
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: Teich
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Canada.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Riddell
authors.affiliation: School of Kinesiology and Health Science and Muscle Health Research Centre, York University, Toronto, Canada.
authors.forename: Tara L
authors.identifier: http://orcid.org/0000-0001-8559-9574
authors.initials: TL
authors.lastname: Haas
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015415:Biomarkers; D002196:Capillaries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D005938:Glucocorticoids / Q000009:adverse effects* / Q000097:blood; D008297:Male; D051379:Mice; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000098:blood supply; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology*; D020011:Protective Agents / Q000494:pharmacology*; D051381:Rats; D013314:Stress, Mechanical; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D015415:Biomarkers; D005938:Glucocorticoids; D020011:Protective Agents; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D011224:Prazosin