Shear stress‐induced angiogenesis in mouse muscle is independent of the vasodilator mechanism and quickly reversible

Abstract

AimIs modulation of skeletal muscle capillary supply by altering blood flow due to a presumptive shear stress response per se, or dependent on the vasodilator mechanism?MethodsThe response to four different vasodilators, and cotreatment with blockers of NO and prostaglandin synthesis, was compared. Femoral artery blood flow was correlated with capillary‐to‐fibre ratio (C:F) and protein levels of putative angiogenic compounds.ResultsAll vasodilators induced a similar increase in blood flow after 14 days, with a similar effect on C:F (1.62 ± 0.05, 1.60 ± 0.01, 1.57 ± 0.06, 1.57 ± 0.07, respectively, all P < 0.05 vs. control 1.20 ± 0.01). Concomitant inhibitors revealed differential effects on blood flow and angiogenesis, demonstrating that a similar response may have different signalling origins. The time course of this response with the most commonly used vasodilator, prazosin, showed that blood flow increased from 0.40 mL min−1 to 0.61 mL min−1 by 28 days (P < 0.05), dropped within 1 week after the cessation of treatment (0.54 mL min−1; P < 0.05) and returned to control levels by 6 weeks. In parallel with FBF, capillary rarefaction began within 1 week (P < 0.05), giving C:F values similar to control by 2 weeks. Of the dominant signalling pathways, prazosin decreased muscle VEGF, but increased its cognate receptor Flk‐1 (both P < 0.01); levels of eNOS varied with blood flow (P < 0.05), and Ang‐1 initially increased, while its receptor Tie‐2 was unchanged, with only modest changes in the antiangiogenic factor TSP‐1.ConclusionHyperaemia‐induced angiogenesis, likely in response to elevated shear stress, is independent of the vasodilator involved, with a rapid induction and quick regression following the stimulus withdrawal.

Alpha adrenergic receptor blockade increases capillarization and fractional O2 extraction and lowers blood flow in contracting human skeletal muscle

“…6 This angiogenic response appears to be independent of the vasodilator used to elevate shear stress. 36 In a previous study, we examined the effect of 4-week regular passive leg movement on muscle capillarization and found a small, but significant increase in capillary supply. 9 Passive leg movement induces an approximate twofold-to threefold increase in blood flow, but also a 20% passive stretch of the muscle, 34 and thus, the effect of shear stress vs. stretch on angiogenesis could not be fully distinguished in this model.…”

“…28 Canonical sprouting angiogenesis is likely responsive to the local metabolic environment and as such is expected to produce a more homogeneous distribution of capillaries relative to the basal condition, whereas the lack of a myocyte response to hyperaemia would suggest a more stochastic angiogenic response, expected to result in an increased capillary supply of similar spatial distribution to that seen prior to intervention. 3,36 Capillary anisotropy (vessel orientation with respect to fibre axis) is dependent on the growth process recruited: abluminal sprouting in response to myocyte signalling will tend to place new vessels according to locations that will alleviate metabolic stress, 37 and hence reduce the heterogeneity of capillary spacing. In contrast, shear stress-induced angiogenesis leads to luminal division, producing vessels with the same orientation as parent vessels and hence maintains the orientation.…”

Microfluidic traction force microscopy to study mechanotransduction in angiogenesis

“…As cell alignment and network formation require cytoskeletal reconstruction, it has been concluded that the flow rates may have been too low to trigger shear stress sensing mechanisms and activate flow‐mediated angiogenesis. Continuous flow stimulation was also found to be required not only to maintain vessel sprouting, but to prevent rapid retraction …”

“…Continuous flow stimulation was also found to be required not only to maintain vessel sprouting, but to prevent rapid retraction. 6,9 There are limitations to be considered in the in vitro models used for shear stress studies. For example, while angiogenesis can occur through sprouting (the migration of EC into tissue toward an angiogenic stimulus) and splitting (the separation of existing vessels by reorganization of EC), most in vitro models focus on the former.…”

The superoxide dismutase mimetic tempol does not alleviate glucocorticoid-mediated rarefaction of rat skeletal muscle capillaries

“…Recent work provided evidence that blood flow is an effective modulator of capillary growth and regression within the skeletal muscle of healthy adult rats, demonstrating that a sustained elevation in blood flow induced capillary growth and that return of blood flow to basal levels provoked capillary loss (Egginton et al. ). Extending this observation, our data suggest that the extent of capillary rarefaction that occurs under pathological conditions such as systemic hypertension (Chen et al.…”