Altered small artery morphology and reactivity in critical limb ischaemia

Abstract

Although the pathophysiology of critical limb ischaemia is poorly understood, there is evidence that the condition of the small arteries may determine the outcome of revascularization procedures. This study was designed to investigate the effects of critical limb ischaemia on the structure and function of the small arteries in the leg. Small arteries (<500 microm) from proximal (non-ischaemic) and distal (ischaemic) sites were obtained from patients undergoing bypass surgery for critical limb ischaemia and mounted in a myograph. Reactivity and morphological measurements were carried out and compared with controls. Control vessels from the thigh and calf showed no difference in media to lumen ratio. However, a comparison of ischaemic and non-ischaemic vessels from the patients with critical limb ischaemia showed significant thinning of the ischaemic vessel wall. Contraction studies using noradrenaline and angiotensin II revealed a significant decrease in the response of ischaemic vessels compared with the non-ischaemic vessels from the same patient. Moreover, these differences in reactivity were still apparent after the responses were corrected for wall thickness. Endothelial function assessed using the endothelium-dependent agonists acetylcholine and bradykinin showed a significantly impaired relaxation response to acetylcholine but not to bradykinin in the ischaemic vessels, and acetylcholine-induced relaxation was not improved after incubation with indomethacin. There was no change in the response to the endothelium-independent cAMP-mediated vasodilator iloprost but a significant impairment to sodium nitroprusside which acts via cGMP. These results suggest that small arteries in critical limb ischaemia are altered in both structure and function, with vessel wall thinning and impaired responses to acetylcholine and sodium nitroprusside.

Alterations in Reactivity of Small Arterioles in Rat Skeletal Muscle as a Result of Chronic Ischaemia

“…The development of smooth muscle dysfunction as a result of 5 weeks of chronic ischaemia in the rat is supported by attenuation of dilation to both these agonists. Hillier et al [9]also demonstrated attenuated SNP responses due to chronic ischaemia in human leg arteries, while Thomas et al [32]showed attenuation of AD vasoactivity in skeletal muscle arterioles of chronic heart failure rats. These effects could also be explained by dysfunction of smooth muscle receptors or second messenger systems (e.g.…”

“…As α 2 -receptors are more prevalent than α 1 -receptors on terminal arterioles in skeletal muscle [30], it may be the former that are affected. Hillier et al [9]reported smaller constrictor responses to NA in arteries of 250–300 µm internal diameter taken from the subcutaneous fat of ischaemic calf muscles in patients compared with control vessels but did not see any pathology in the vascular smooth muscle. These vessels, however, may not have experienced the same ischaemia as those of the deeper muscular tissue.…”

“…chronic heart failure [17], is taken to indicate impairment or damage to endothelium. Hillier et al [9]found that critical leg ischaemia in human patients rendered arteries from subcutaneous fat less reactive to ACh than those from healthy patients. These attenuated responses to ACh may be due to specific dysfunction of the endothelial muscarinic receptors [18].…”

“…The latter, however, does not supply the affected lower limb musculature in these patients. Impairment of both endothelium and vascular smooth muscle function by low flow has been indicated by depressed ACh- and cGMP-mediated responses in subcutaneous fat arteries from critically ischaemic limbs [9], in which deprivation of flow is very severe. In rats with ligation of the iliac artery, terminal arterioles in muscles ischaemic for up to 2 weeks failed to dilate in response to muscle contractions [10], but it is not known whether changes in vascular endothelium and/or smooth muscle underlie this adaptation.…”

A New Model of Peripheral Arterial Disease: Sustained Impairment of Nutritive Microcirculation and Its Recovery by Chronic Electrical Stimulation

“…This, in turn, is regulated by the capacity of resistance arterial vessels to dilate during muscle contractions, for which nitric oxide (NO) generated by increases in blood flow and shear stress [25] is a requirement [10] , [28] . Patients with peripheral vascular disease have decreased levels of systemic nitric oxide [5] and impaired endothelial‐dependent dilation of both conduit [45] and resistance vessels [18] , [29] . In rat hindlimb muscles, acute ischemia attenuated endothelium‐dependent NO‐mediated vasodilation [41] , and chronic ischemia for 2 weeks following iliac artery ligation caused precapillary arterioles to lose their ability to dilate in response to muscle contractions [19] or to endothelial‐dependent vasoactive agents [23] .…”