Sickle cell disease (SCD) patients experience an elevated burden of psychosocial stressors. This study was designed to determine the impact of SCD on the hemodynamic response to acute behavioral stress. We utilized humanized sickle cell disease (HbSS) and hemoglobin A control mice (HbAA). Blood pressure, heart rate, and locomotor activity were measured by telemetry. Baseline 24-hour blood pressure was significantly lower in HbSS compared to HbAA (p<0.05) mice similar to humans with SCD. Mice were exposed to cage switch stress (CSS), a model of acute psychosocial stress. CSS rapidly induced a pressor response in all groups. HbSS mice exhibit a blunted rise in systolic blood pressure (46.6 ± 4.8 vs. 24.3 ± 3.5 mmHg-hours, p=0.036), and diastolic blood pressure (47.2 ± 4.6 vs. 21.0 ± 3.2 mmHg-hours, p=0.021) compared to HbAA mice. CSS induced a similar rise in heart rate and activity in HbSS and HbAA, suggesting that both genotypes experienced a similar level of acute stress. These results suggest that SCD dampens the normal physiological pressor response to acute stress. We then hypothesized that SCD mice would display enhanced sensitivity to α1-adrenoreceptor-mediated vasoconstriction but this enhancement would be absent in resistance arteries. Vascular reactivity of isolated aortic and resistance mesenteric artery (100-150μm 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 significantly 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) compared to HbAA. In contrast, resistance mesenteric arteries from HbSS and HbAA mice displayed similar sensitivity to α1-adrenoreceptor-mediated vasoconstriction as indicated by comparable EC50 and Emax (p>0.05). Graded concentration responses to KCl were similar between genotypes. Aorta of HbSS mice exhibited increased α1A-adrenoreceptor mRNA 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 (p>0.05). α1B-adrenoreceptor expression was similar in aorta of HbSS mice and HbAA mice (p>0.05) and was not detected in resistance mesenteric arteries. Additionally, α1D-adrenoreceptor expression was similar in aorta (p>0.05) and resistance mesenteric arteries (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. Similar sensitivity to α1-adrenoreceptor-mediated vasoconstriction in resistance arteries suggests that increased vasodilator mechanisms may be responsible for the blunted cardiovascular responses to stress in HbSS mice.