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. cerebral circulation; endocannabinoids; cannabinoid receptors; TRPV1 channel; neurovascular unit THE CEREBRAL VASCULATURE HAS two main homeostatic functions: 1) to adjust the local blood supply to the eventually rapidly changing metabolic demands of neurons; and 2) to maintain an optimal extracellular environment in the brain. The former function is realized by the regulation of the local cerebral blood flow (CBF), whereas the latter is achieved by the maintenance of the blood-brain barrier (BBB) and related transport mechanisms. The endocannabinoid system has been implicated as an important regulatory component in both of these cerebrovascular functions. The roles of endocannabinoids and cannabinoid receptors in the BBB have been reviewed recently (237). Here we aim to overview our knowledge on the endocannabinoid-mediated regulation of cerebral circulation.

Ferulic acid attenuates brain microvascular endothelial cells damage caused by oxygen-glucose deprivation via punctate-mitochondria-dependent mitophagy

“…Accumulating evidences indicates that the dysfunction of BMECs can promotes the formation of blood clots and causes local cerebrovascular contraction, convulsion and cerebral ischemic anoxia (Benyo et al, 2016). The action of BMECs leads to the initiation and development of both BBB breakdown and the pathological process of vascular dementia (Pasyk et al, 2004).…”

Maternal alcohol exposure during mid-pregnancy dilates fetal cerebral arteries via endocannabinoid receptors

“…The endocannabinoid system (eCBS) consists of eCB-producing enzymes, eCB ligands, eCB receptors (mostly CB1 and CB2 types), and the eCB degradation machinery (Lu & Mackie, 2016). Endocannabinoid production, functional activity of CB1 and CB2 receptors, and eCB breakdown within the vascular smooth muscle have all been reported (Benyó, Ruisanchez, Leszl-Ishiguro, Sándor, & Pacher, 2016; Czikora et al, 2012; Rajesh et al, 2008). It remains unknown whether alcohol in general, and prenatal alcohol exposure in particular, affects the components of the vascular eCB system and its regulation of cerebrovascular contractility.…”

Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity

“…For example, tamoxifen use in humans (Yang et al, 2013) and research of CBR inverse agonists demonstrate that both groups of compounds increase bone mineralization, sensitivity to nociception and may result in depression (Idris and Ralston, 2010; Buggy et al, 2011; Nazarali and Narod, 2014; Azizi-Malekabadi et al, 2015). Furthermore, endogenously produced cannabinoids (e.g., endocannabinoids) are important modulators of cerebral blood flow (Benyo et al, 2016) and agonist activation of CB2Rs reduces infarct volume and improves functional outcome in experimental stroke (England et al, 2015). Antagonism of CB2R function by SERMs might thus contribute to the increased stroke incidence sometimes observed with this class of drugs (Rizzoli et al, 2011).…”