α1‐Adrenoreceptor‐Mediated Vasoconstriction is Enhanced in the Aorta but not Resistance Arteries of Humanized Sickle Cell Mice

In patients with sickle cell disease (SCD), psychosocial stress is associated with the onset of potentially fatal vaso‐occlusive crises. We recently reported that SCD mice display a blunted blood pressure response to acute psychosocial stress, a phenomenon that may contribute to the onset of vaso‐occlusive crises. However, the mechanisms underlying blunted cardiovascular responses to stress in SCD mice are unclear. We hypothesized that aorta of SCD mice would display enhanced sensitivity to α1‐adrenoreceptor‐mediated vasoconstriction but this enhancement would be absent in resistance arteries. Male 16 week old humanized SCD (HbSS) and genetic control (HbAA) mice were utilized for all experiments. Vascular reactivity of isolated aortic and resistance mesenteric artery (100–150 μm diameter) rings to phenylephrine (PE) and potassium chloride (KCl) were examined using wire myography. Aortae of HbSS mice demonstrated enhanced sensitivity to α1‐adrenoreceptor‐mediated vasoconstriction as evidenced by lower EC50 (−6.22 ± 0.14 vs. −6.90 ± 0.04 log[PE, M], p=0.002) and elevated Emax (118.7 ± 3.2 vs. 155.9 ± 5.2 %KCl, p<0.001) in response to PE compared to HbAA mice. In contrast, resistance mesenteric arteries from HbSS mice displayed similar sensitivity to α1‐adrenoreceptor‐mediated vasoconstriction as indicated by comparable EC50 (−5.81 ± 0.12 vs. −5.80 ± 0.07 log[PE, M], p>0.05) and Emax (133.9 ± 13.4 vs. 118.3 ± 6.7 %KCl, p>0.05) in response to PE versus HbAA mice. Graded concentration responses to KCl were similar between genotypes. In order to determine the mechanism responsible for differences in sensitivity to α1‐adrenoreceptor‐mediated vasoconstriction between conduit and resistance arteries of HbSS mice, α1‐adrenoreceptor expression was examined using RT‐qPCR. Aortae of HbSS mice exhibited increased α1A‐adrenoreceptor expression compared to HbAA mice (1.00 ± 0.18 vs. 2.25 ± 0.40, p=0.016), while resistance mesenteric arteries of HbSS mice displayed similar α1A‐adrenoreceptor expression compared to HbAA mice (1.00 ± 0.07 vs. 1.04 ± 0.08, p>0.05). α1B‐adrenoreceptor expression was similar in aortae of HbSS mice and HbAA mice (1.00 ± 0.12 vs. 1.09 ± 0.17, p>0.05) and was not detected in resistance mesenteric arteries. Additionally, α1D‐adrenoreceptor expression was similar in aortae (1.00 ± 0.18 vs. 1.37 ± 0.21, p>0.05) and resistance mesenteric arteries (1.00 ± 0.06 vs. 1.13 ± 0.09, p>0.05) of HbSS mice and HbAA mice. These findings suggest that enhancement of arterial sensitivity to α1‐adrenoreceptor‐mediated vasoconstriction in HbSS mice is specific to conduit arteries and results from increased α1A‐adrenoreceptor expression. Furthermore, similar sensitivity to α1‐adrenoreceptor‐mediated vasoconstriction in resistance arteries of HbSS versus HbAA mice suggests that other mechanisms are responsible for blunted cardiovascular responses to stress in HbSS mice, such as enhanced vasodilators. Support or Funding Information This work was supported by funding from the National Institutes of Health ‐ U01 HL117684 to Drs. Jennifer and David Pollock, F30 DK107194 to Brandon Fox, F31 DK111067 to Randee Sedaka, ASN Ben J. Lipps Research Fellowship to Malgorzata Kasztan, and partially supported by MSTP T32 GM008361. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .