Abstract
Angiogenesis is an essential process for normal skeletal muscle function. There is a growing body of evidence suggesting that thrombospondin-1 (TSP-1), a potent antiangiogenic protein in tumorigenesis, is an important regulator of both physiological and pathological skeletal muscle angiogenesis. We tested the hypothesis that chronic exposure to a TSP-1 mimetic (ABT-510), which targets the CD36 TSP-1 receptor, would decrease skeletal muscle capillarity as well as alter the balance between positive and negative angiogenic proteins under basal conditions. Osmotic minipumps with either ABT-510 or vehicle (5% dextrose) were implanted subcutaneously in the subscapular region of C57/BL6 mice for 14 days. When compared to the vehicle treated mice, the ABT-510 group had a 20% decrease in capillarity in the superficial region of the gastrocnemius (GA), 11% decrease in the plantaris (PLT), and a 35% decrease in the soleus (SOL). ABT-510 also decreased muscle protein expression of vascular endothelial growth factor (VEGF) in both the GA (−140%) and SOL (−62%); however there was no change in VEGF in the PLT. Serum VEGF was not altered in ABT-510 treated animals. Endogenous TSP-1 protein expression in all muscles remained unaltered. Tunnel staining revealed no difference in muscle apoptosis between ABT-510 and vehicle treated groups. These data provide evidence that the anti-angiogenic effects of TSP-1 are mediated, at least in part, via the CD36 receptor. It also suggests that under physiologic conditions the TSP-1/CD36 axis plays a role in regulating basal skeletal muscle microvessel density.
Highlights
Physiologic angiogenesis and homeostasis of adult blood vessels is a complex process that is highly regulated by a balance between positive and negative angiogenic proteins
While there is a substantial body of evidence on the role positive angiogenic factors, such as vascular endothelial growth factor (VEGF) [1,2,3], the role of negative angiogenic factors is incomplete and poorly understood [4]
These data are consistent with the anti-angiogenic function of TSP-1 and, more importantly, support the notion that TSP-1 through its CD36 receptor is a critical regulator of skeletal muscle capillarity under physiologic conditions
Summary
Physiologic angiogenesis and homeostasis of adult blood vessels is a complex process that is highly regulated by a balance between positive and negative angiogenic proteins. While there is a substantial body of evidence on the role positive angiogenic factors, such as vascular endothelial growth factor (VEGF) [1,2,3], the role of negative angiogenic factors is incomplete and poorly understood [4]. First discovered for its role in wound healing and platelet activation, it has important roles in apoptosis, inflammation, nitric oxide signaling, and inhibition of positive angiogenic proteins [6,7,8,9,10]. Acting through CD36 (one of its receptors), TSP-1 has been shown to prevent endothelial cell adhesion, growth, and migration, as well as increase apoptosis [11,12,13]. A reduction in TSP-1 has been shown to increase tumor vessel growth, whereas pharmacological administration of several different TSP-1 mimetics has helped decrease tumor size and disease progression in animal models [14,15,16,17]
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