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.
Highlights
Elevated circulating levels of glucocorticoids (GC) occurs in individuals with poorly controlled diabetes, metabolic syndrome or Cushing syndrome [1,2]
We report for the first time that CORT-mediated skeletal muscle capillary rarefaction was associated with lower levels of Ang-1, but not Vascular endothelial growth factor-A (VEGF-A) mRNA, and that capillary loss was prevented with 2W of concurrent prazosin treatment
Elevated CORT resulted in a decrease in Ang-1 expression, which may correspond with the observed rarefaction of capillaries within skeletal muscle
Summary
Elevated circulating levels of glucocorticoids (GC) occurs in individuals with poorly controlled diabetes, metabolic syndrome or Cushing syndrome [1,2]. A prolonged pathophysiological increase in GC elicits a loss (rarefaction) of pre-existing capillaries within skeletal muscle [3]. Shear stress activates pro-survival factors such as Akt [9] and endothelial nitric oxide synthase (eNOS) [10]. This in turn will increase the production of nitric oxide (NO) [10], which exerts vasodilatory, anti-thrombotic and anti-inflammatory functions [11]. Vascular endothelial growth factor-A (VEGF-A) production is increased by elevated shear stress [12] and exerts autocrine endothelial cell survival signaling [13]
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