Hyperlipidemia Disrupts Cerebrovascular Reflexes and Worsens Ischemic Perfusion Defect

Abstract

Hyperlipidemia is a highly prevalent risk factor for coronary and cervical atherosclerosis and stroke. However, even in the absence of overt atherosclerosis, hyperlipidemia disrupts endothelial and smooth muscle function. We investigated the impact of hyperlipidemia on resting-brain perfusion, fundamental cerebrovascular reflexes, and dynamic perfusion defect during acute focal ischemia in hyperlipidemic apolipoprotein E knockout mice before the development of flow-limiting atherosclerotic stenoses. Despite elevated blood pressures, absolute resting cerebral blood flow was reduced by 20% in apolipoprotein E knockout compared with wild type when measured by [ 14 C]-iodoamphetamine technique. Noninvasive, high spatiotemporal resolution laser speckle flow imaging revealed that the lower autoregulatory limit was elevated in apolipoprotein E knockout mice (60 vs. 40 mm Hg), and cortical hyperemic responses to hypercapnia and functional activation were attenuated by 30% and 64%, respectively. Distal middle cerebral artery occlusion caused significantly larger perfusion defects and infarct volumes in apolipoprotein E knockout compared with wild type. Cerebrovascular dysfunction showed a direct relationship to the duration of high-fat diet. These data suggest that hyperlipidemia disrupts cerebral blood flow regulation and diminishes collateral perfusion in acute stroke in the absence of hemodynamically significant atherosclerosis.

Rho-Kinase Inhibition Improves Ischemic Perfusion Deficit in Hyperlipidemic Mice

“…Peri-infarct depolarizations typically induced a transient hyperemia in mildly ischemic cortex, and hypoperfusion in more severely ischemic regions ( Figure 3A). Because high-fat diet is known to diminish PID occurrence, 4 we usually detected only 1 PID during the 60-minute imaging period in vehicle controls ( Figure 3B). We, therefore, pooled all ROCK inhibitor treatment groups to gain statistical power for nonparametric testing, and found that ROCK inhibition was associated with fewer PID occurrence.…”

“…The impact of peri-infarct depolarizations (PIDs) on ischemic perfusion defect was calculated as % change in the area of cortex with residual CBFp30% from immediately before a PID to just after its recovery, as described in detail previously. [12][13][14] In addition, using the preischemic speckle contrast images we determined the t c À 1 values as a measure of resting CBF, as described previously, 4,15 and calculated the resting cerebrovascular resistance (CVR) using the formula CVR (%) ¼ MABP/CBF, where both MABP and CBF were expressed relative to the vehicle group. In a separate cohort of ApoE KO mice treated with vehicle or fasudil for 4 weeks (n ¼ 3 each), we determined the plasma lipid profile (Table 1).…”

“…4 We have recently shown that hyperlipidemic vascular dysfunction is associated with markedly larger perfusion defects on focal cerebral arterial occlusion. 4 A large body of evidence suggests that upregulation of Rho-associated kinase (ROCK) activity is one mechanism by which hyperlipidemia leads to vascular dysfunction. [5][6][7][8] Numerous studies have also shown that ROCK inhibition improves stroke outcome in otherwise normal animals, 9 and that the mechanism involves endothelium-dependent improvement in ischemic tissue perfusion presumably by augmenting the collateral blood supply.…”

Probucol inhibits LPS-induced microglia activation and ameliorates brain ischemic injury in normal and hyperlipidemic mice

“…It is well known that hyperlipidemia induces inflammation in the brain [5][6][7] and that hyperlipidemia exacerbates the ischemic brain damage that is linked to neuroinflammation [8,9] . There is also considerable evidence that hyperlipidemia contributes to the disruption of cerebrovascular reflexes and the breakdown of the blood-brain barrier [45,46] . Therefore, the modulation of hyperlipidemia and neuroinflammation via probucol may be an effective therapeutic strategy for reducing the effects of both hyperlipidemia and ischemic stroke.…”

Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke

“…In other studies, hypercholesterolemia was sufficient to produce vascular dysfunction in animal models including primates. For example, in models where cerebral arteries had minimal or no detectable atherosclerotic lesions, hypercholesterolemia reduced resting CBF, the influence of basally-produce NO on vascular tone, 114–116 as well as agonist- and platelet-induced endothelium-dependent relaxation. 117–120 Vasoconstrictor responses to endothelin-1 were substantially increased in hyperlipidemic mice.…”