Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia

Aug 5, 2021Journal of the American Heart Association

Circadian Rhythm Disruption May Harm Blood Vessel Repair in Blocked Leg Arteries

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Abstract

Circadian rhythm disorders may impair angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia.

Plasma vascular endothelial growth factor and circulating endothelial progenitor cells exhibited a circadian rhythm in control mice, which was diminished under jet-lag conditions.
Jet-lag conditions led to reduced tissue capillary formation and blood perfusion recovery in hind limb ischemia models.
Downregulation of vascular endothelial growth factor expression in ischemic tissue and plasma was observed in the jet-lag model.
Increased expression of clock genes after ischemic injury was noted, yet the jet-lag condition inhibited the expression of specific clock genes (Cry1 and Cry2).
Double-knockout mice showed decreased capillary density and impaired blood perfusion recovery in hind limb ischemia.
In human umbilical vein endothelial cells, gene knockdown resulted in reduced proliferative capacity, migration ability, and tube formation, indicating impaired angiogenesis.

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Background Circadian rhythm disorders, often seen in modern lifestyles, are a major social health concern. The aim of this study was to examine whether circadian rhythm disorders would influence angiogenesis and blood perfusion recovery in a mouse model of hind limb ischemia. Methods and Results A jet-lag model was established in C57BL/6J mice using a light-controlled isolation box. Control mice were kept at a light/dark 12:12 (12-hour light and 12-hour dark) condition. Concentrations of plasma vascular endothelial growth factor and circulating endothelial progenitor cells in control mice formed a circadian rhythm, which was diminished in the jet-lag model (<0.05). The jet-lag condition deteriorated tissue capillary formation (<0.001) and tissue blood perfusion recovery (<0.01) in hind limb ischemia, which was associated with downregulation of vascular endothelial growth factor expression in local ischemic tissue and in the plasma. Although the expression of clock genes (ie,,, and) in local tissues was upregulated after ischemic injury, the expression levels of cryptochrome (Cry) 1 and Cry2 were inhibited by the jet-lag condition. Next,anddouble-knockout mice were examined for blood perfusion recoveries and a reparative angiogenesis.anddouble-knockout mice revealed suppressed capillary density (<0.001) and suppressed tissue blood perfusion recovery (<0.05) in the hind limb ischemia model. Moreover, knockdown ofin human umbilical vein endothelial cells was accompanied by increased expression ofand decreased expression of. This was associated with decreased proliferative capacity, migration ability, and tube formation ability of human umbilical vein endothelial cells, respectively, leading to impairment of angiogenesis. Conclusions Our data suggest that circadian rhythm disorder deteriorates reparative ischemia-induced angiogenesis and that maintenance of circadian rhythm plays an important role in angiogenesis. P P P Clock Bmal1Cry Cry1Cry2Cry1Cry2P P CRY1/2WEE1HOXC5

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Adverse Effect of Circadian Rhythm Disorder on Reparative Angiogenesis in Hind Limb Ischemia

Abstract

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