Low Energy Shock Wave Therapy Induces Angiogenesis in Acute Hind-Limb Ischemia via VEGF Receptor 2 Phosphorylation

Abstract

ObjectivesLow energy shock waves have been shown to induce angiogenesis, improve left ventricular ejection fraction and decrease angina symptoms in patients suffering from chronic ischemic heart disease. Whether there is as well an effect in acute ischemia was not yet investigated.MethodsHind-limb ischemia was induced in 10–12 weeks old male C57/Bl6 wild-type mice by excision of the left femoral artery. Animals were randomly divided in a treatment group (SWT, 300 shock waves at 0.1 mJ/mm2, 5 Hz) and untreated controls (CTR), n = 10 per group. The treatment group received shock wave therapy immediately after surgery.ResultsHigher gene expression and protein levels of angiogenic factors VEGF-A and PlGF, as well as their receptors Flt-1 and KDR have been found. This resulted in significantly more vessels per high-power field in SWT compared to controls. Improvement of blood perfusion in treatment animals was confirmed by laser Doppler perfusion imaging. Receptor tyrosine kinase profiler revealed significant phosphorylation of VEGF receptor 2 as an underlying mechanism of action. The effect of VEGF signaling was abolished upon incubation with a VEGFR2 inhibitor indicating that the effect is indeed VEGFR 2 dependent.ConclusionsLow energy shock wave treatment induces angiogenesis in acute ischemia via VEGF receptor 2 stimulation and shows the same promising effects as known from chronic myocardial ischemia. It may therefore develop as an adjunct to the treatment armentarium of acute muscle ischemia in limbs and myocardium.

Effect of shock waves on macrophages: A possible role in tissue regeneration and remodeling

“…The promotion of regenerative events instead of simply healing processes by ESWT may have multiple applications and is presently considered of particular interest in cardiology, where restoring of tissue integrity, instead of fibrous tissue, is crucial for cardiac function. Consistent with this, recent evidence indicates that ESWT improves ventricular function in ischemic heart failure [6,32].…”

“…More recently, the positive effects of ESWT on soft tissues and the vascular bed has made it possible its application in clinical practice also for some andrologic disturbances (induratio penis plastic, erectyle disfunctions) [5]. Regenerative and trophic effects have also been demonstrated in ischemic and related heart diseases, although at present ESWT application in this field is still experimental [6] [7].…”

Shock wave treatment after hindlimb ischaemia results in increased perfusion and M2 macrophage presence

“…The diameter of the applicator's membrane is 4.5 cm and 300 impulses were delivered to the ischaemic area with an energy flux density of 0.1 mJ/mm 2 at a frequency of 5 Hz. The rationale for the treatment parameters is experience from previous studies (Tepekoylu et al ., ; Holfeld et al ., ,b). No adverse effects have been observed at these energy levels.…”

Low-energy shock wave preconditioning reduces renal ischemic reperfusion injury caused by renal artery occlusion

“…Low-energy shock waves have been used in many fields to reduce the damage induced by tissue ischemia or to improve recovery after ischemia. The technique induces angiogenesis in ischemic muscle due to vascular endothelial growth factor (VEGF) receptor 2 14 , enhances ischemic tissue survival, blood flow, and angiogenesis 15 . It also increases the efficacy of cell therapy in chronic hind limb ischemia 16 , improves microcirculation blood flow of ischemic limbs in patients with peripheral arterial disease 17 , and improves perfusion and cardiac function in patients with ischemic heart failure 18 .…”