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Humanized Sickle Cell Disease Mice Display an Increased Sensitivity to α1‐adrenergic Mediated Vasoconstriction

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. Vascular dysfunction is a common pathway contributing to the diverse pathologies seen in SCD, however, the mechanisms are not fully understood. We utilized a novel mouse globin knockout, human sickle cell gene knockin mouse (βS/βS) and the heterozygous control mouse (βA/βS). The α1 adrenergic and endothelin (ET‐1) pathways are activated in SCD. We hypothesized that thoracic aorta from SCD mice would demonstrate increased sensitivity to α1‐adrenergic mediated vasoconstriction with increased aortic endothelin (ET‐1) expression. Thoracic aortae were isolated from 12‐week‐old male βS/βS or βA/βS mice and mounted on wire myographs (n=3 per group) to assess vasoconstriction. In addition, ET‐1 expression was analyzed using qRT‐PCR (n=5 per group). Cumulative concentration‐response curves were generated for phenylephrine (PE) and KCl to assess vasoconstriction as well as acetylcholine (ACh) and sodium nitroprusside (SNP) for vasodilation. Vasoconstriction to PE was significantly increased in βS/βS mice compared to βA/βS (90±5 vs. 38±7 %Max KCl, p=0.004), without a change in vasodilation between groups. ET‐1 expression was similar in both groups (0.98±0.23 vs. 1.00±0.18 ΔΔCT). Thus, the thoracic aorta of SCD mice display exaggerated α1‐mediated vasoconstriction without a change in vasodilation or ET‐1 expression. These data indicate that SCD enhances vascular α1‐adrenergic mediated signaling in the thoracic aorta, which provides mechanistic insight into a link between stress and vaso‐occlusive crises in SCD patients. Funded by T32 HL007918 to BMF, U01 HL117684 to DMP and JSP, and partially supported by MSTP T32GM008361.