Circulating neutrophils maintain physiological blood pressure by suppressing bacteria and IFNγ-dependent iNOS expression in the vasculature of healthy mice

Abstract

Whether leukocytes exert an influence on vascular function in vivo is not known. Here, genetic and pharmacologic approaches show that the absence of neutrophils leads to acute blood pressure dysregulation. Following neutrophil depletion, systolic blood pressure falls significantly over 3 days (88.0 ± 3.5 vs 104.0 ± 2.8 mm Hg, day 3 vs day 0, mean ± SEM, P < .001), and aortic rings from neutropenic mice do not constrict properly. The constriction defect is corrected using l-nitroarginine-methyl ester (L-NAME) or the specific inducible nitric oxide synthase (iNOS) inhibitor 1400W, while acetylcholine relaxation is normal. iNOS- or IFNγ-deficient mice are protected from neutropenia-induced hypotension, indicating that iNOS-derived nitric oxide (NO) is responsible and that its induction involves IFNγ. Oral enrofloxacin partially inhibited hypotension, implicating bacterial products. Roles for cyclooxygenase, complement C5, or endotoxin were excluded, although urinary prostacyclin metabolites were elevated. Neutrophil depletion required complement opsinization, with no evidence for intravascular degranulation. In summary, circulating neutrophils contribute to maintaining physiological tone in the vasculature, at least in part through suppressing early proinflammatory effects of infection. The speed with which hypotension developed provides insight into early changes that occur in the absence of neutrophils and illustrates the importance of constant surveillance of mucosal sites by granulocytes in healthy mice.

Genetic and Pharmacologic Inhibition of the Chemokine Receptor CXCR2 Prevents Experimental Hypertension and Vascular Dysfunction

“…30 For example, infiltration of neutrophils is important to initially activate or fully stimulate monocytes/macrophages in the vessel wall but has no effect on arterial hypertension induced by angiotensin II. 6 T cells but not B cells have been reported to promote vascular dysfunction and hypertension in mice after angiotensin II infusion or DOCA-salt stress.…”

Association between circulating specific leukocyte types and incident chronic kidney disease: the Atherosclerosis Risk in Communities (ARIC) study

“…at a faster rate. Activated neutrophils may suppress nitric oxide synthesis (iNOS) expression 51 , which could profoundly deteriorate kidney function 52 .…”

Lysozyme M–Positive Monocytes Mediate Angiotensin II–Induced Arterial Hypertension and Vascular Dysfunction

“…40 Telemetric blood pressure recordings revealed that ablation of LysM ϩ cells not only improved vascular dysfunction but also nearly abolished the increase in systolic blood pressure in response to ATII, paralleled by a strikingly decreased rate of vascular fibrosis and medial hypertrophy ( Figure 6). However, not only monocytes/macrophages but also neutrophils might contribute to blood pressure regulation 41 and, via their myeloperoxidase activity, to blood pressure increase in response to ATII. 42 Additionally, LysM ϩ neutrophils play a role in the progression of early atherosclerotic lesions, as demonstrated in monocyte-depleted ApoE Ϫ/Ϫ LysM egfp/egfp mice.…”