Functional and anatomical evidence of cerebral tissue hypoxia in young sickle cell anemia mice

Abstract

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

The severity of anaemia depletes cerebrovascular dilatory reserve in children with sickle cell disease: a quantitative magnetic resonance imaging study

“…However, there is a limit to which a cerebral vessel can dilate, which is referred to as cerebrovascular dilatory reserve. In a recent study in a transgenic mouse model, young SCD mice exhibited cerebral tissue hypoxia, which was associated with chronic anaemia and reduced vascular reserve (Cahill et al, 2016). episode of acute chest syndrome, aplastic crises, splenic sequestration or nocturnal hypoxaemia) may predispose children with SCD to acute cerebral tissue hypoxia and subsequent stroke (Wang, 2007).…”

“…episode of acute chest syndrome, aplastic crises, splenic sequestration or nocturnal hypoxaemia) may predispose children with SCD to acute cerebral tissue hypoxia and subsequent stroke (Wang, 2007). In a recent study in a transgenic mouse model, young SCD mice exhibited cerebral tissue hypoxia, which was associated with chronic anaemia and reduced vascular reserve (Cahill et al, 2016). Hence, it is important to assess CBF and cerebrovascular dilatory reserve in children with SCD to understand the extent of haemodynamic compensation available and potentially predict the risk for ischaemic stroke.…”

Acute and chronic stage adaptations of vascular architecture and cerebral blood flow in a mouse model of TBI

“…Following hypercapnia, there was a 6-minute break between measurements to allow for return to normal physiological state. [17,18]. As TBI may cause edema [19] and influence tissue T1, affecting CBF measurements [18], T1 was mapped in the same 2 mm-thick coronal section using an inversion recovery fast spin-echo sequence (TR = 5000 ms, TE = 11ms, inversion times = 50, 100, 200, 400, 800, 1600, 3200 ms).…”

A mathematical model of cerebral blood flow control in anaemia and hypoxia

“…sickle cell disease), the cerebrovasculature remodels to provide larger diameter vessels (Cahill et al . ; Cahill et al . ) to facilitate a persistent increase in CBF, which reverses on correction of anemia by transfusion (Hulbert et al .…”

“…Over the long term (e.g. sickle cell disease), the cerebrovasculature remodels to provide larger diameter vessels (Cahill et al 2017;Cahill et al 2019) to facilitate a persistent increase in CBF, which reverses on correction of anemia by transfusion (Hulbert et al 2017). Of interest, reduction of this chronic elevation of CBF by transfusion also reduces the incidence of stroke, providing indirect evidence of the enhancement of cerebral oxygen delivery by transfusion .…”