The CB1 Receptor In Vascular Smooth Muscle Cells Is Involved In The Regulation Of The Physiological Functions Of The Cardiovascular System And The Mechanism Of Action In The Occurrence Of Cerebral Ischemic Diseases

The endocannabinoid system(eCB),is composed of endocannabinoid ligands,cannabinoid receptors and the enzymes for endocannabinoid biosynthesis and degradation.The eCB system is involved in regulation of various physiological reactions,such as learning and memoryemotion et al.Endocannabinoids work through their receptors.There are two main types of the cannabinoid receptors,including cannabinoid I receptor(CB1)and cannabinoid II receptor(CB2).The CB1receptors are mainly distributed in the central nervous system,while the CB2 receptors are mainly distributed in the peripheral and some immune organs.Recent research indicated that the CB1 receptor is expressed not only in the central nervous system,but also in the cardiovascular system,such as myocardial cells,endothelial cells and vascular smooth muscle cells.Previous researches reported that endocannabinoids can decrease blood pressure,diastolic blood vessels,inhibit myocardial contraction,anti-inflammatory,and protect endothelial from cardiovascular damage.These researches revealed that the endocannabinoids has potential clinical value in the treatment of cardiovascular diseases.Therefore,it is particularly urgent to clarify the concrete regulation mechanism on the cardiovascular system of the endocannabinoids system in physiological and pathological conditions.Studies have shown that endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions.But in the pathological state,the expression of the endocannabinoid system is increased.It is reported that endogenous cannabinoids have a significant antihypertensive effect in hypertensive rat models,and the endocannabinoid system can reduce ischemic injury in models of cerebral ischemia.It was also found that the knockout of CB1 receptors can induce aggravation of cerebral ischemic injury and significantly reduce of cerebral blood flow in the penumbra area,indicating that CB1 receptors of the endocannabinoid system play a very important role in the neuroprotection,through regulate vascular function.Besides there are researchers reported that endocannabinoids can directly vasodilate or contract blood vessels via the CB1 receptor on blood vessels,but the molecular mechanism is not yet clear.Cannabinoid receptors are widely distributed in the cardiovascular system.This study focuses on the function of CB1 receptor on vascular smooth muscle cells.The role of this receptor in cardio-cerebral vascular regulation has not been reported.In this study,a conditional knockout technique was used to construct a mouse model that specifically lacking CB1 receptors in vascular smooth muscle cells.The research analyzed the physiological and pathological functions of this receptor.By measuring the basal blood pressure of CNR1 SMAKO mice and wildtype mice,and intervention of cannabinoid agonists on blood pressure,analyzing the effects of CB1 agonists on blood pressure in animals and the role and mechanism of this receptor in the regulation of vascular tone,establishing cerebral ischemia model to research the role of CB1 receptor in smooth muscle cells in the pathology,we have obtained the following results:(1)By measuring blood pressure in awake mice,we found that there is no significant difference in basal blood pressure between CNR1SMAKO mice and wildtype mice.Cannabinoid agonists can reduce the blood pressure,but-there is no significant difference between CNR1SMAKO mice and control mice,indicating that the regulation of blood pressure by the smooth muscle cell CB1 receptor under normal physiological conditions is not important.(2)We found that cannabinoid agonists can cause significant vasodilation in cannabinoid vascular tone modulation assays.In the vasoconstriction stimulated by norepinephrine(NE),the cannabinoid receptor agonist WIN55212-2 can cause vasodilation,and the relaxation rate of CNR1SMAKO mice is significantly lower than that of wildtype mice,indicating that the vascular smooth muscle cell CB1 receptor participates in the relaxation response.(3)By establishing a model of cerebral ischemia,it was found that the ischemic infarct volume of CNR1SXMAKO mice was significantly greater than that of wild mice,indicating that CB1 receptors in smooth muscle cells have an important protective effect in cerebral ischemia.In summary,this study focused on the functional of CB1 receptor in regulating blood pressure,vascular tone,as well as in pathological conditions such as cerebral ischemia.Our results indicate that under normal physiological conditions,the CB1 receptor in vascular smooth muscle does not play an important role in vascular smooth muscle system,but under certain pathological conditions,such as during cerebral ischemic disease,endocannabinoids can regulates vascular tone via the vascular smooth muscle CB1 receptor,thereby regulating cerebral blood flow,and playing a protective role in these states.Our research results will provide new ideas and theoretical basis for clinical treatment of cardiovascular and cerebrovascular diseases.