| Background and objective:Hypoperfusion, usually induced by cerebral vascular stenosis or occlusion, is one of the direct causes of ischemic stroke and vascular dementia. Recently, with ageing aggravating, the incidence of ischemic stroke and vascular dementia in our country showed an increasing tendency, posing threat to human health. It is acknowledged that collateral circulation compensation,determines the therapeutic effects of these diseases. If collateral circulation can form as soon as possible after cerebral ischemia, it will be greatly protective to ischemic tissue and neurological function. Unfortunately, opened collateral circulation after cerebrovascular stenosis or occlusion usually can not maintain normal perfusion. Then, collateral vascular remodeling(angiogenesis and arteriogenesis) would be promoted to provide extra blood supply, and that is why promoting reconstruction of collateral circulation becomes increasingly attractive..There are many researches on cerebral circulation reconstruction. In animal studies, different combinations of unilateral or bilateral ligation of carotid arteries and the vertebral artery was used to explore change of collateral arteriogenesis, cerebral circulation reserve capacity and cerebral blood flow after hypoperfusion. However, considering that cerebral artery stenosis is a progressive process, these animal models cannot simulate the pathophysiological processes of cerebral blood flow after cerebral artery stenosis. Therefore, it is important tp establish a suitable animal model of progressive decline of cerebral blood flow for studying the development and reconstruction of collateral circulation. Meanwhile, a large number of studies indicated that perivascular nerve can influence angiogenesis and arteriogenesis. But how cerebral sympathetic nerve affects collateral circulation reconstruction under conditions of cerebral hypoperfusion, remains unknown. Hence, research on key step of cerebral perivascular sympathetic regulation, aimed at finding out specific targeting molecule and exploring a kind of therapy for accelerating reconstruction of cerebral collateral circulation, would be of great significance for protecting ischemic brain tissue,neurological functional recovery and long-term prognosis.In the present study, we firstly established a progressive cerebral hypoperfusion canine model using successive embolization to explore the process, time course and degree of cerebral circulation construction, providing basic theory for time of clinical treatment; Secondly, unilateral carotid artery ligation was performed in rats to explore the effect of sympathetic nerve on cerebral artery collateral circulation reconstruction, and lay the foundation for further study of sympathetic regulation of collateral circulation reconstruction.Main contents:Part One:Experimental study of the reconstruction of cerebral circulation in a progressive cerebral hypoperfusion canine modelWe first established a progressive cerebral hypoperfusion canine model by successive embolization.1. To explore the relationship between the variation of cerebral blood flow and cerebral collateral circulation reconstruction after successive embolization;2. To explore the effect of interval time on cerebral collateral circulation reconstruction, and the relationship between the interval time and the cerebral radiographic and neurological function changes;Part Two:The effect of sympathetic denervation on rat cerebral collateral circulation reconstruction after cerebral hypoperfusion1. To explore the influence of sympathetic denervation on reconstruction of leptomeningeal collateral vessels and Willis circle artery under condition of cerebral hypoperfusion;2. To explore the influence of sympathetic denervation on cerebral blood flow, brain infarction volume and neurological function when recurrent ischemia happens in rat brain under condition of cerebral hypoperfusion.Main methods:Part One:1.18 hybrid adult dogs were divided into four groups according to random number table, including group A, B, C and D. We performed interventional embolism in left and right vertebral artery, and left and right internal carotid artery simultaneously or successively. Group A (n=3)as normal control,Group B(n=5)was successively embolized every one week, group C(n=5)every two week, and group D(n=5)was simultaneously embolized;2. Changes of cerebral blood flow were detected by perfusion weighted MRI imaging after embolization;3.Cerebral radiographic changes were tested by MRI or CT;4.Cerebral collateral circulation reconstruction were observed by DSA after embolization;5. Neurological function was evaluated by overall performance categories(OPC).Part Two:1. A total of 84 healthy adult male SD rats were randomly divided into four groups: including arterial ligation combined with denervation group(combined group) (n=21), artery ligation group(n=21), denervation group(n=21) and sham group(n=21).Every group were divided into three subgroup:A, B, C, each possess 7 rats;2. Cerebral hypoperfusion model was established by right common carotid artery ligation, while denervation was performed by surgical removal of the ipsilateral superior cervical sympathetic ganglion;3. In subgroup A, diameters of leptomeningeal collateral vessels and Willis circle artery were observed by latex perfusion;4. In subgroup B, immunohistochemical staining was carried out aimed to observe the thickness changes of the right leptomeningeal collateral vessels;5. In subgroup C, rats were performed permanent middle cerebral artery occlusion (pMCAO), and cerebral blood flow were detected with LDF, neurological damage assessment were carried out using neurological scores 24h postoperation, and cerebral infarct volume was tested by TTC staining.Main results:Part One:1. Cerebral blood flow:Cerebral blood flow in group D decreased sharply; Cerebral blood flow in group B and C decreased gradually, and began to increase after complete embolization, and recover to normal after eight weeks; Cerebral blood flow in group C decreased more mildly than group B;2. DSA tests:when the left and right vertebral artery were successively embolized, internal carotid artery dilation and collateral circulation of basal cerebral arteries opened in group B and group C, but there was no new vascular formation; Then left and right internal carotid artery were further embolized, and new vascular formed in group B and C, and group C more obviously; After 8w, intracranial cerebral vascular enlarged and increased obviously in both group B and C;3. Imaging tests:multiple and massive infarction were seen in group D. Some animals showed basal ganglia infarct in group B, and no infarction was seen in group C;4. Neurological function tests:group A:levell; group B:all level 1 except one level 2; group C:level 1; group D:level 5, and all the animals in died 2.5-8h postoperatively.Part Two:1. Changes of brain vessel diameter:the diameters of right leptomeningeal collateral vessels in combined group were smaller significantly than in artery ligation group, and bigger than in denervation group and sham group; and the diameters of right Willis circle artery in combined group were smaller significantly than in artery ligation group;2. Thickness of brain vessel:the thickness of right leptomeningeal collateral vessels in combined group is thinner compared with artery ligation group, and thicker than denervation group and sham group;3. pMCAO test:The ratio of cerebral blood flow to basic level in combined group was significantly lower than in artery ligation group; Neurological function scoring indicated that scores in combined group were significantly higher than in artery ligation group; TTC staining showed cerebral infarct volume in combined group was significantly higher than in artery ligation group.Conclusions:1. After successive embolization of internal carotid artery and vertebral artery, cerebral blood flow decreased gradually. When the four arteries were completely embolized, cerebral blood flow began to increase, and recover to normal after eight weeks; cerebral circulation and blood flow reserve can be completely reconstructed by formation of collateral artery in 8 weeks; there is a close relationship between the degree and time of circulation reconstruction, it will take 2 weeks to reconstruct abundant and effective collateral circulation.2. Sympathetic denervation can impair the cerebral collateral circulation reconstruction after cerebral hypoperfusion, and leading to greater infarction volume and worse neurological function when recurrent ischemia occurs. |
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