Our current study has identified two important findings. First, ischemic stroke induces long-term changes in myogenic tone of MCAs at both ischemic and non-ischemic hemispheres. Second, ischemic stroke induces long-term changes in reactivity to vasoactive agents in MCAs at both ischemic and non-ischemic hemispheres. These findings may provide insight for the development of novel therapies stroke treatment.
Increasing evidence has demonstrated that transient focal cerebral ischemia affects myogenic tone not only in local cerebrovasculature but also contralateral vasculature at acute stage after ischemic stroke [6
]. In the present study, we determined myogenic response of MCAs at 2 days or 2 weeks after experimental ischemic stroke as magnetic resonance imaging study has indicated that postischemic hyperperfusion peaked at 2 days and resolved 1 week after ischemic stroke using a similar model [12
]. Our result concurs with the previous publications, demonstrating a bilateral vasculature dysfunction after transient focal cerebral ischemia [6
]. In addition, our study identified a long-term impairment of myogenic response in MCAs after focal cerebral ischemia.
Focal cerebral ischemia induced not only impairment of myogenic response but also a change in reactivity to vasoactive agents in MCAs. Constriction and dilation of large arteries in the brain regulates cerebral vascular resistance and cerebral microvascular pressure [15
]. Diminished cerebral arterial responsiveness to vasoconstrictor 5-HT, abolition of endothelium-dependent relaxation, and diminished distensibility of cerebral vasculatures have been observed after transient focal cerebral ischemia in experimental stroke models [6
]. In the present study, MCAs from both ischemic and contralateral hemispheres of stroke animals had similar dilation responses to ACh as MCAs from sham controls at 2 days post-reperfusion. However, at 2 weeks post-reperfusion, both ischemic and contralateral MCAs from stroke animals showed a lesser dilatory response than MCAs from sham controls. Interestingly, the dilative action of SNP, an endothelium-independent vasodilator induces a robust dilation in normal MCAs, was significantly diminished in MCAs after transient focal cerebral ischemia, suggesting that an endothelium-independent mechanism could also contribute to the ischemic stroke-induced vasculature dysfunction. Consistently, studies have shown that loss of myogenic activity after ischemic stroke was associated with a decrease in filamentous actin in vascular smooth muscle [14
]. In ischemic stroke patients, SNP treatment has been found to improve local CBF given at a dose which reduced mean arterial blood pressure by 10 mmHg [17
]. In the present ex vivo analysis, we have identified a markedly diminishment of vasodilative action of SNP in MCAs after ischemic stroke. Further in vivo
studies are needed to validate our finding and its significance in term of ischemic stroke.
Maintenance of constant CBF as a result of autoregulation caused by a combination of myogenic, neuronal, and metabolic mechanisms is critical for brain function [15
]. Thus, it might not be surprising that pathological conditions such as ischemic stroke could disrupt neurovascular coupling and consequently induce cerebral vasculature dysfunction in the ischemic hemisphere. Increasing evidence has indicated occlusion of a cerebral artery could induce both hemodynamic and cellular change beyond the ischemic territory [19
]. During focal cerebral artery occlusion, the circulatory system can compensate for the reduction of focal CBF using collateral circulation and autoregulatory mechanisms, which causes hemodynamic perturbations and a redistribution of CBF [20
]. Flow territory maps in patients of internal carotid artery occlusion showed significant differences in flow territories of contralateral internal carotid artery and vertebrobasilar arteries compared with those in control subjects [22
]. In experimental stroke models, transient unilateral hemodynamic stress has found to induce a transient increase in CBF velocities in the opposite hemisphere and delayed cleavage of neuronal caspase 3 in both ischemic and contralateral side cortices, although their cause-effect relationship at the non-ischemic side remained unknown. [23
]. In addition, endothelial dysfunction has been found in the peripheral mesenteric resistance artery after experimental ischemic stroke in rats [24
]. It is till unclear how focal cerebral ischemic damage induces a global vasculature dysfunction. A recent study has indicated that ischemic stroke could trigger an inflammatory process and an increase of cytokine expression in plasma, which might contribute to the impairment of vasculature function [8
The acute damage of myogenic reactivity and autoregulatory capacity of cerebral vasculature after ischemic stroke might contribute to reperfusion injury and edema formation at the ischemic territory [5
]. On the other hand, the long-term impairment of autoregulation of global cerebral vasculature might not only make the patients prone to recurrence of ischemic stroke but also contribute to the progression of vascular dementia after ischemic stroke. Stroke is the first leading cause of long-term disability in the United States. Epidemiological studies have shown that the prevalence of dementia in ischemic stroke patients is 4 to 12 times higher than controls [26
]. In addition, a progressive course of cognitive function decline has been suggested [27
]. Brain function is tightly coupled with CBF autoregulation and thus cognitive function is by default coupled to the functional capacity of brain's autoregulatory capabilities. Cognitive and sensorimotor stimulation induces increases in CBF that are associated with increased metabolic demand [31
]. Ischemic stroke-induced long-term vascular dysfunction might compromise the coupling between the metabolic requirements of brain and CBF, thereby affecting cognitive function. Indeed, evidence shows that drugs used for the treatment of systemic vascular disorders such as hypertension have effects on cerebral vasculature function and modify the progression of dementia [32
In summary, the present study demonstrates that transient focal cerebral ischemia could induce long-term impairment of spontaneous myogenic tone in MCAs at both ischemic and non-ischemic areas. The loss of dilatory responses of MCAs to ACh and SNP suggest that both endothelial-dependent and -independent mechanisms could contribute to the global vascular dysfunction induced by ischemic stroke. Our study places further emphasis on studies of vascular protection for the treatment of ischemic stroke. Chronic vascular protection through enhancement of endothelial function and suppression of thrombosis has been a traditional approach for primary and secondary prevention of stroke [5
]. Understanding the molecular mechanisms underlying the long-term effect of ischemic stroke on cerebral vasculature could eventually lead to development of more effective therapeutics for both acute treatment of ischemic stroke and prevention of vascular dementia after stroke.