Prazosin Can Prevent Glucocorticoid Mediated Capillary Rarefaction

• Published in: PloS one 2016-11, Vol.11 (11), p.e0166899-e0166899
• Main Authors: Mandel, Erin R, Dunford, Emily C, Trifonova, Anastassia, Abdifarkosh, Ghoncheh, Teich, Trevor, Riddell, Michael C, Haas, Tara L
• Format: Article
• Language: English
• Subjects: a1-Adrenergic receptors; Adrenergic receptors; AKT protein; Angiogenesis; Angiogenesis Inducing Agents - metabolism; Angiopoietin; Angiopoietin-1 - genetics; Angiopoietin-1 - metabolism; Animals; Apoptosis; Biology and Life Sciences; Biomarkers; Capillaries - drug effects; Capillaries - metabolism; Capillaries - pathology; Cell survival; Corticosterone; Drinking water; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Extracellular signal-regulated kinase; Gelatinase A; Gene Expression; Glucocorticoids; Glucocorticoids - adverse effects; Glucocorticoids - blood; Kinases; Male; Matrix metalloproteinase; Medicine and Health Sciences; Metalloproteinase; Mice; Models, Animal; mRNA; Muscle, Skeletal - blood supply; Muscles; Myoblasts - drug effects; Myoblasts - metabolism; Nitric oxide; Phosphorylation; Physical Sciences; Prazosin; Prazosin - pharmacology; Protective Agents - pharmacology; Rarefaction; Rats; Reduction; RNA; Rodents; Shear stress; Shear stresses; Signaling; Skeletal muscle; Steroids (Organic compounds); Stress, Mechanical; Thrombospondin 1 - genetics; Thrombospondin 1 - metabolism; Transforming growth factor-b1; Transforming growth factors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Water treatment
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0166899

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.