E ndothelin-1 (ET)-1, a 21-aa peptide produced by endothelial and other cells, is one of the most potent vasoconstrictors.1,2 Plasma ET-1 is increased in patients with essential hypertension and in hypertension associated with systemic disorders, in atherosclerosis and heart failure, as well as in other cardiovascular and metabolic disorders, and in chronic kidney disease.3 ET-1 plays a role in the development of hypertension by causing vascular damage and inflammation. 4,5 Transgenic mice overexpressing ET-1 specifically in endothelial cells (eET-1) present endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. 6,7 The immune system plays a role in hypertension and vascular injury. [8][9][10] The innate immune system is involved in angiotensin (Ang) II, deoxycorticosterone acetate (DOCA)/ salt, and aldosterone-induced hypertension and vascular damage. [11][12][13] Ang II, DOCA/salt, and aldosterone infusion caused an increase in vascular monocyte/macrophage infiltration. Ang II and DOCA/salt-induced hypertension and vascular remodeling, oxidative stress, and inflammation were blunted in a model with reduced monocytes/ macrophages, the osteopetrotic (Op) mouse, which is deficient in macrophage colony stimulating factor (CSF) 11,12 because of a thymidine (T) insertion in the coding region of the colony stimulating factor (Csf1) gene that generates a stop codon 21 bp downstream.14 Similarly, aldosterone-induced endothelial dysfunction and vascular oxidative stress were decreased in Csf1Op/+ mice. 13 The innate immune system could play a role in ET-1-induced vascular injury, because the inflammation observed in eET-1 is characterized by an increase in vascular monocyte/macrophage infiltration. However, this remains to be demonstrated.To test the hypothesis that innate immunity participates in ET-1-induced vascular injury, we studied whether vascular injury induced by increased expression of ET-1 is prevented in eET-1 mice crossed with Csf1Op/+ mice that have reduced monocyte/macrophage-dependent inflammation.Abstract-Transgenic mice with endothelium-specific endothelin-1 (ET-1) overexpression exhibit endothelial dysfunction and vascular remodeling, oxidative stress, and inflammation. We previously observed that monocytes/macrophages play a role in angiotensin II, aldosterone, and deoxycorticosterone acetate/salt-induced vascular remodeling, oxidative stress, and inflammation using a model with reduced monocytes/macrophages, the osteopetrotic (Op) mouse, which has a mutation in the macrophage colony stimulating factor (Csf1) gene. However, it is unknown whether monocytes/ macrophages are implicated in adverse vascular effects of ET-1. We hypothesized that reduction in monocytes/ macrophages would blunt ET-1-induced vascular injury. We performed a study on 4-to 6-month-old male mice with endothelium-specific ET-1 overexpression (eET-1), reduction in CSF1 (Csf1Op/+ ), or both (eET-1/Csf1Op/+ ), and their wildtype littermate control mice. There was no difference in systolic blood pre...

In human atherosclerosis, which is associated with elevated plasma and coronary endothelin (ET)-1 levels, ET A receptor antagonists improve coronary endothelial function. Mice overexpressing ET-1 specifically in the endothelium (eET-1) crossed with atherosclerosis-prone apolipoprotein E knockout mice (Apoe 2/2 ) exhibit exaggerated high-fat diet (HFD)-induced atherosclerosis. Since endothelial dysfunction often precedes atherosclerosis development, we hypothesized that mice overexpressing endothelial ET-1 on a genetic background deficient in apolipoprotein E (eET-1/Apoe 2/2 ) would have severe endothelial dysfunction. To test this hypothesis, we investigated endothelium-dependent relaxation (EDR) to acetylcholine in eET-1/Apoe 2/2 mice. EDR in mesenteric resistance arteries from 8-and 16-week-old mice fed a normal diet or HFD was improved in eET-1/Apoe 2/2 compared with Apoe 2/2 mice. Nitric oxide synthase (NOS) inhibition abolished EDR in Apoe 2/2 . EDR in eET-1/Apoe 2/2 mice was resistant to NOS inhibition irrespective of age or diet. Inhibition of cyclooxygenase, the cytochrome P450 pathway, and endothelium-dependent hyperpolarization (EDH) resulted in little or no inhibition of EDR in eET-1/Apoe 2/2 compared with wild-type (WT) mice. In eET-1/Apoe 2/2 mice, blocking of EDH or soluble guanylate cyclase (sGC), in addition to NOS inhibition, decreased EDR by 36 and 30%, respectively. The activation of 4-aminopyridine-sensitive voltage-dependent potassium channels (K v ) during EDR was increased in eET-1/Apoe 2/2 compared with WT mice. We conclude that increasing eET-1 in mice that develop atherosclerosis results in decreased mutual dependence of endothelial signaling pathways responsible for EDR, and that NOS-independent activation of sGC and increased activation of K v are responsible for enhanced EDR in this model of atherosclerosis associated with elevated endothelial and circulating ET-1.

Erythropoietin-induced adverse vascular effects are dependent on preexisting elevated ET-1 expression. Exercise training prevented erythropoietin-induced adverse vascular effects in part by inhibiting ET-1 overexpression-induced oxidative stress, inflammation and immune activation.

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