Immune Cell‐Mediated Vasomotor Dysfunction in Large Vessels During Hypercholesterolemia

Abstract

Hypercholesterolemia, a risk factor for the development of atherosclerosis, elicits inflammation and endothelial cell dysfunction in large arteries. The adaptive immune system has been implicated in the development of lesions, but it remains unclear whether lymphocytes contribute to the early hypercholesterolemia-induced arterial dysfunction. Our hypothesis was that hypercholesterolemia elicits large vessel endothelial dysfunction through an immune-mediated mechanism. Wire myography was employed to assess vasodilation and constriction responses of aortic rings in four groups of mice: wild-type (WT) mice on a normal diet, WT mice on a high cholesterol diet for 2 weeks (HC), lymphocyte deficient (SCID) mice on HC, and a SCID-HC group that received splenocytes from WT mice 5 days prior to observation. Endothelium-independent contraction to phenylephrine did not differ between the groups. Aortic rings also exhibited similar endothelial-independent dilation responses to sodium nitroprusside regardless of diet or immune-competency. In contrast, HC led to an impaired endothelium-dependent vasodilation response to acetylcholine in WT mice. This hypercholesterolemia-induced dysfunction was absent in lymphocyte-deficient mice. However, administration of splenocytes to immunodeficient SCID-HC mice restored the hypercholesterolemia-induced impairment of endothelium-dependent vasodilation. Our findings indicate that lymphocytes contribute to hypercholesterolemia-induced endothelial cell dysfunction in large arteries long before the development of atherosclerotic plaques. (Supported by R01 HL26441