| Endocannabinoid system(eCB)is composed of endocannabinoids,cannabinoid receptors,and enzymes responsible for the synthesis and degradation of endogenous cannabinoid ligands.Endocannabinoids mainly participate in various physiological responses in the body through the cannabinoid receptors.Cannabinoid receptor 1(CB1R)and cannabinoid receptor 2(CB2R)are two most classic cannabinoid receptors.CB1R is mainly expressed in the central nervous system.Besides,it is also expressed in the cardiovascular system,including myocardial tissues,blood vessels and blood cells.CB2R is mainly expressed in immune system and is supposed to regulate immune responses.As cannabinoid receptors are widely distributed in different tissues,increasing research has reported about cannabinoids in the central and peripheral system.Many studies have shown that almost all cells in the brain may participate in the process that cannabinoids regulate cerebral circulation mechanism in the central system.In addition to the tight regulation mechanism of neurons,a target is the cerebrovascular system.In the peripheral system,cannabinoids have been extensively reported in regulating cardiovascular physiological functions.Many reports show that cannabinoids can relax blood vessels,lower blood pressure and inhibit myocardial contraction.Therefore,Exploring the effects of cannabinoids on the regulation of cerebral circulation and the regulation of cardiovascular physiological functions has an potential clinical value for brain protection and treatment of cardiovascular diseases.Many studies have shown that endocannabinoid system may have many complex regulated effects on cardiovascular function through CB1R under physiological conditions.Besides,it is an complex and important progress that cannabinoids participate in the regulation of cerebral circulation through the CB1R to maintain neurological homeostasis.Under pathological conditions such as hypertension disease samples,the expression of endocannabinoids and their receptors is increased;In the model of ischemic brain injury,the infarct volume is increased in CB1R complete knockout mice,and cerebral blood flow decreased in the ischemic penumbra.Therefore,we hypotheses that CB1R play an important protective role in ischemic brain injury.Endocannabinoids maintain blood supply to focal brain injury areas by activating CB1R,which reduced post-ischemic injury.Its protective mechanism may be derived from neurogenic or myogenic.We focused on the role of CB1R in vascular smooth muscle cells in cerebral circulation and cardiovascular effects.In this project,we first constructed conditional CB1R knockout mice(CNR1SMKO)that tissue specifically delete CB1 in vascular smooth muscle cells to investigate the role of this receptor in physiological states including vascular tone,blood pressure and cerebral blood flow regulation.The research include the following items:(1)Detecting isolated vascular tone of CNR1SMKO and CTR mice,in order to explore the role of CB1R on vascular smooth muscle cells in regulating vascular tension through cannabinoids;(2)Measurement of the blood pressure of CNR1SMKO mice and CTR mice,and explore the role of the receptor in regulating blood pressure through cannabinoids;(3)Cerebral blood flow recording of CNR1SMKO mice and CTR mice treated with CB1R agonist,to explore the role of this receptor in regulating cerebral circulation through cannabinoids.We get the following results:(1)First,this research measure the mesenteric and cerebrovascular tone in mice by an in vitro microvascular techniques,to explore the role of vascular CB1R in regulating vascular tone regulation to cannabinoids.The result shows that norepinephrine(NE)can cause vasoconstriction in a concentration-dependent manner,indicating that the absence of CB1R in vascular smooth muscle cells has no significant effect on vasoconstriction function.In the diastolic response test,we found WIN55212-2 can relax the mesenteric blood vessels in a concentration-dependent manner.At 3 μM and 10 WIN55212-2,the relaxation efficiency of CNR1SMKO mice is significantly lower than CTR group,The results show that CB1R of vascular smooth muscle cells participate in the regulation of mesenteric vasodilation by WIN55212-2;2-arachidonoylglycerol(2-AG)can relax mesenteric vessels in dose-dependent manner,but no statistical difference in CNR1SMKO group and CTR group,indicating that CB 1R of vascular smooth muscle cells participate in the regulation of mesenteric vasodilation by 2-AG;Narachidonic tetradilute ethanolamide(AEA)can relax mesenteric vessels in dosedependent manner,but no statistical difference in CNR1SMKO group and CTR group,indicting that CB1R in vascular smooth muscle cells don’t participate in the regulation of mesenteric vasodilation by 2-AG,or there are some compensation approaches.The result of cerebral vascular tone show sthat WIN55212-2 can mediate cerebral vasodilation effect,but CB1R in vascular smooth muscle cells does not participate the diastolic effect of WIN55212-2 on cerebrovascular.(2)This research detected blood pressure in mice of awake movement by a noninvasive blood pressure system,to investigate whether vascular CB1R is involved in the regulation of cannabinoids on blood pressure.In the NE-induced blood pressure regulation,the cannabinoid receptor agonist WIN55212-2 can reduce blood pressure.After intravenous injection of WIN55212-2,the blood pressure of CNR1SMKO group mice and CTR group mice was significantly lower than before.At 32 min after intravenous administration of WIN55212-2,the blood pressure of CTR group mice was significantly lower than CNR1SMKO group mice.The result shows that WIN55212-2 can decrease blood pressure in the awake state by NE-induced high blood pressure,and CB1R of vascular smooth muscle cells participate in the regulation of cannabinoids on blood pressure.(3)This research monitored cerebral blood flow in CNR1SMKO and CTR mice in the MCA region by means of a cerebral blood flow meter.After intravenous injection of WIN55212-2,cerebral blood flow significantly increased in the MCA region of mice,but there was no statistical difference between the control group and the knockout group.The result indicates that WIN55212-2 can increase cerebral blood flow,and CB1R of vascular smooth muscle cells can not affect the regulation of cerebral blood flow by cannabinoids.In summary,the results of this study indicate that the relaxation effect of cannabinoids is mediated by CB1R in vascular smooth muscle and can significantly decrease blood pressure,may be can no effect reglution of cerebral blood flow.These results indicate that CB1R in blood vessels can significantly reduce blood pressure by regulating part of the vasodilation effect which can be used as a potential treatment for hypertension.Cannabinoid receptor agonist can relax cerebral blood vessels and increase cerebral blood flow,suggesting that this pathway has a certain protective effect in ischemic brain injury diseases.In short,to research of the physiological function of CB1R on blood vessels has some mean of reference for the study of cannabinoids on regulating the cerebral circulation mechanism and cardiovascular function,and afford a new theoretical basis that cannabinoids as a new drug for treating cardiovascular and cerebrovascular diseases. |
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