Endocannabinoids in cerebrovascular regulation

Abstract

The cerebral blood flow is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms under physiological conditions, and a large body of recent evidence indicates that inflammatory pathways have a major influence on the cerebral blood perfusion in certain central nervous system disorders, like hemorrhagic and ischemic stroke, traumatic brain injury, and vascular dementia. All major cell types involved in cerebrovascular control pathways (i.e., smooth muscle, endothelium, neurons, astrocytes, pericytes, microglia, and leukocytes) are capable of synthesizing endocannabinoids and/or express some or several of their target proteins [i.e., the cannabinoid 1 and 2 (CB1 and CB2) receptors and the transient receptor potential vanilloid type 1 ion channel]. Therefore, the endocannabinoid system may importantly modulate the regulation of cerebral circulation under physiological and pathophysiological conditions in a very complex manner. Experimental data accumulated since the late 1990s indicate that the direct effect of cannabinoids on cerebral vessels is vasodilation mediated, at least in part, by CB1 receptors. Cannabinoid-induced cerebrovascular relaxation involves both a direct inhibition of smooth muscle contractility and a release of vasodilator mediator(s) from the endothelium. However, under stress conditions (e.g., in conscious restrained animals or during hypoxia and hypercapnia), cannabinoid receptor activation was shown to induce a reduction of the cerebral blood flow, probably via inhibition of the electrical and/or metabolic activity of neurons. Finally, in certain cerebrovascular pathologies (e.g., subarachnoid hemorrhage, as well as traumatic and ischemic brain injury), activation of CB2 (and probably yet unidentified non-CB1/non-CB2) receptors appear to improve the blood perfusion of the brain via attenuating vascular inflammation.

Keywords: TRPV1 channel; cannabinoid receptors; cerebral circulation; endocannabinoids; neurovascular unit.

Fig. 1.

Regulatory pathways of the cerebral circulation. A continuous balance between the oxygen demand and oxygen supply of the brain is essential for physiological neuronal functions. Cerebrovascular resistance is tightly regulated by myogenic, endothelial, metabolic, and neural mechanisms in response to changes in neuronal activity or disturbances of the cardiorespiratory system. In case of an imbalance between the oxygen demand and supply, the cerebral ischemic response (Cushing reflex) is activated and increases the perfusion pressure of the brain.

Fig. 2.

Main biosynthetic pathways and targets of 2-arachydonylglycerol (2-AG) and anandamide. Phospholipase C (PLC) converts phosphatidylinositol (PI) to diacylglycerol (DAG), which is further converted to 2-AG by DAG lipase (DAGL). Anandamide is synthesized by phospholipase D (PLD) from N-arachidonoyl phosphatidylethanolamine (NAPE), which is produced from phosphatidylethanolamine (PEA) by N-acyltransferase (NAT). 2-AG and anandamide can activate both cannabinoid 1 (CB₁R) and cannabinoid 2 receptors (CB₂R). In addition, anandamide was reported to interact with the transient receptor potential vanilloid type 1 (TRPV₁) ion channel. Activation of CB₁R and CB₂R induces cellular actions via heterotrimeric G protein-mediated pathways, whereas the intracellular signaling of TRPV₁ channels is initiated by Ca²⁺ influx and cell membrane depolarization (ΔEm).

Fig. 3.

Expression of cannabinoid receptors and TRPV₁ channels in cells involved in cerebrovascular regulation. Top inset: cannabinoid receptors and TRPV₁ channels in the wall of pial and penetrating arteries (E, endothelium; PM, pia mater; PVN, perivascular nerve; SM, smooth muscle). Bottom inset: expression of cannabinoid receptors and TRPV₁ channels in the neurovascular unit and related cells of the cerebral microcirculation (A, astrocyte; M, microglia; NT, nerve terminal; P, pericyte; PN, postsynaptic neuron).