African Ancestry-linked DARC Deficiency Promotes Systemic Inflammation and Endothelial Dysfunction

Hypertension is the leading risk factor for cardiovascular disease, and it disproportionately affects individuals of African descent (IAD). Although socioeconomics and health disparities contribute to these racial differences, they do not fully explain the increased burden, supporting the contribution of ancestry-linked genetic factors, including the Duffy Antigen Receptor for chemokines (DARC). A single-nucleotide polymorphism in the DARC promoter (GATA-1) prevents DARC expression on red blood cells (RBC). Homozygous carriers exhibit the Duffy null genotype, present in 95% of IAD. DARC binds circulating chemokines on RBC and regulates inflammation; however, its direct role in vascular function and blood pressure regulation remains ill-defined. We hypothesized that loss of DARC drives inflammation, impairs vascular function, and elevates blood pressure. We used a DARC knock-out mouse model (DARC-/-), which replicates the DARC-negative genotype. Blood pressure (BP) measurements using telemetry revealed no alterations in baseline mean arterial pressure (MAP) in DARC-/- mice compared to their wild-type controls. Mesenteric artery reactivity measured by wire myography showed impaired endothelium-dependent relaxation to acetylcholine. Inhibition of nitric oxide synthase with L-NAME reduced relaxation and abolished the difference in vasodilatation between DARC+/+ and DARC-/- mice, supporting a reduced NO bioavailability in DARC-/- mice. In contrast, smooth muscle-dependent relaxation to sodium nitroprusside remained intact in all groups, indicating preserved smooth muscle function. Additionally, vasocontraction in response to phenylephrine was significantly increased in DARC-/- mice. Plasma chemokine analysis showed significantly reduced CXCL1 and CCL11 in DARC-/- mice, consistent with altered chemokine handling in the absence of DARC. In contrast, proinflammatory cytokines, including IL-17A, IL-6, IL-1β, and TNF-α, were significantly increased, reflecting a shift towards a proinflammatory cytokine profile. Flow cytometry of peripheral blood indicated that DARC loss does not alter major circulating lymphocyte populations or CD3+ and CD4+ T cell subsets. To increase the translational relevance of our mouse model, we performed bone marrow transplant (BMT) using WT and DARC-/- donors to determine whether these effects were mediated by RBC-expressed DARC. Mice receiving DARC-/- bone marrow developed endothelial dysfunction and elevated systolic blood pressure compared to WT-WT controls, indicating that RBC DARC is sufficient to impair vascular function and increase blood pressure. Chemokine and cytokine profiling in BMT mice mirrored the intact mice, with CXCL1 and CCL11 reduced and proinflammatory cytokines elevated in DARC-WT recipients, further supporting that RBC DARC loss drives these effects. In conclusion, DARC deficiency impairs endothelial function and promotes a pro-inflammatory environment. BMT studies demonstrate that RBC DARC loss induces endothelial dysfunction and raises systolic blood pressure, suggesting that RBC-associated DARC plays a key role in mediating these effects. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.