Abstract
Sickle cell disease (SCD) is associated with a high incidence of ischemic stroke. SCD is characterized by hemolytic anemia, resulting in limited oxygen (O2) delivery to tissues, increased nitric oxide (NO) scavenging, and impaired cerebrovascular hemodynamics. Cerebral blood flow (CBF) is a key metric in determining proper O2 delivery to cerebral tissue. CBF is tightly regulated to maintain constancy of cerebral perfusion by both local mechanisms and autonomic control. Independent from cerebral autoregulation, the influence of the partial arterial carbon dioxide (PaCO2) tension on CBFis known as the cerebrovascular CO2 responsiveness and reflects the vasodilatory capacity of the cerebral vasculature or cerebrovascular reserve capacity. Since cerebrovascular CO2 responsiveness is oxygen dependent and has been related to an increased stroke risk in microvascular diseases such as SCD. This study determines the effects of changes in hemoglobin O2 affinity in cerebrovascular CO2 responsiveness in SCD. CBF was measured using a laser Doppler probe placed over the cortex. The Hb O2 affinity was manipulated via intravenous administration of 5‐hydroxymethyl‐2‐furfural (5HMF), to decrease the Hb‐O2 affinity of homozygous Townes transgenic SCD mice form 32 mmHg to 16 mmHg. To estimate the cerebrovascular reserve capacity animals were challenged with hypercapnia (5% CO2/21% O2 over 20 minutes) for three cycles. Animals with increased Hb O2 affinity showed increased cerebrovascular reserve capacity compared to animals with normal Hb O2 affinity. In conclusion, increasing Hb‐O2 affinity of sickle cell mice protects cerebrovascular CO2 responsiveness, suggesting a increased cerebrovascular reserve capacity which might protect from stroke in SCD.Support or Funding InformationThis work was supported by the NIH Heart Lung and Blood Institute under Grants T32‐HL105373, R01‐HL126945, and the DOD DMRDP under Grant W81XWH‐18‐1‐0059
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