Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction

Abstract

H. Molecular mechanisms of the angiogenic effects of low-energy shock wave therapy: roles of mechanotransduction. Am J Physiol Cell Physiol 311: C378 -C385, 2016. First published July 13, 2016; doi:10.1152/ajpcell.00152.2016.-We have previously demonstrated that low-energy extracorporeal cardiac shock wave (SW) therapy improves myocardial ischemia through enhanced myocardial angiogenesis in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris. However, the detailed molecular mechanisms for the SW-induced angiogenesis remain unclear. In this study, we thus examined the effects of SW irradiation on intracellular signaling pathways in vitro. Cultured human umbilical vein endothelial cells (HUVECs) were treated with 800 shots of low-energy SW (1 Hz at an energy level of 0.03 mJ/mm 2 ). The SW therapy significantly upregulated mRNA expression and protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). The SW therapy also enhanced phosphorylation of extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt. Furthermore, the SW therapy enhanced phosphorylation of caveolin-1 and the expression of HUTS-4 that represents ␤1-integrin activity. These results suggest that caveolin-1 and ␤1-integrin are involved in the SW-induced activation of angiogenic signaling pathways. To further examine the signaling pathways involved in the SW-induced angiogenesis, HUVECs were transfected with siRNA of either ␤ 1-integrin or caveolin-1. Knockdown of either caveolin-1 or ␤ 1-integrin suppressed the SW-induced phosphorylation of Erk1/2 and Akt and upregulation of VEGF and eNOS. Knockdown of either caveolin-1 or ␤1-integrin also suppressed SW-induced enhancement of HUVEC migration in scratch assay. These results suggest that activation of mechanosensors on cell membranes, such as caveolin-1 and ␤1-integrin, and subsequent phosphorylation of Erk and Akt may play pivotal roles in the SW-induced angiogenesis. shock wave; mechanotransduction; angiogenesis; caveolin-1; ␤1-integrin SHOCK WAVES (SW) have been clinically introduced for lithotripsy since the 1980s; urinary stones are broken up by highenergy SW (7). The waveform of an SW is similar to that of a blast wave, which is composed of discontinuous compression of leading shock propagating with supersonic speed, subsequent rarefaction, and negative pressure (27). Over the past 20 years, low-energy SW therapy has also been put into clinical application (3,17). We have previously demonstrated that low-energy SW (about 10% of the energy used for urolithotripsy treatment) significantly upregulated vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs) (25). Low-energy SW therapy has also been reported to enhance nitric oxide (NO) production via activation of endothelial NO synthase (eNOS) in vitro (23,24). We have demonstrated that extracorporeal low-energy cardiac SW therapy enhances angiogenesis and contractile function in a porcine model of chronic myocardial isc...

Functional Outcome at Short and Middle Term of the Extracorporeal Shockwave Therapy Treatment in Lateral Epicondylitis: A Case-Series Study

“…Particularly interesting, for future prospective, is the study of Vitali et al [38]. The authors highlighted that the combination of ESWT and dietary supplementation produced an increased bioavailability of the supplement to the tendon tissue, due to the neo-angiogenic properties [39,40].…”

Extracorporeal Shockwave Therapy Treatment in Upper Limb Diseases: A Systematic Review

“…The use of focal ultrasonography improved the functionality of shockwaves [43], as well as the use of DS, because of their advantage to be not pharmacologic and to contain compounds with modulatory effects on inflammation [3]. The combination of ESWT and DS produce an increased bioavailability of the supplement to the tendon tissue, due to the neo-angiogenic properties [51,52], which results in a decrease in the use of NSAIDs [11].…”

Terapia de ondas de choque focal para osteoartrose de joelho: um ensaio clínico randomizado duplo-cego

“…11 Medical use of ESWT began in 1980 for lithotripsy, and in the 1990s it began to be used for musculoskeletal disorders. 11 ESWT creates a micro-trauma which induces angiogenesis, [12][13][14][15][16] potentially reducing inflammation and improving the quality of cartilage. 9,[17][18][19][20] It decreases nerve conduction velocity, which could explain the immediate antinociceptive effect.…”