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Published in final edited form as: Microvasc Res. 2020 Sep 24;133:104077. doi: 10.1016/j.mvr.2020.104077

A Cannabinoid Type 2 (CB2) Receptor Agonist Augments NOS-Dependent Responses of Cerebral Arterioles during Type 1 Diabetes

Lauren Van Hove 1, Kirsten R Kim 1, Denise M Arrick 1, William G Mayhan 1
PMCID: PMC7704564  NIHMSID: NIHMS1631963  PMID: 32979391

Abstract

While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D). Our goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)-dependent dilation of cerebral arterioles during T1D. In vivo diameter of cerebral arterioles in nondiabetic and T1D rats was measured in response to an eNOS-dependent agonist (adenosine 5’-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-D-aspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 hour following JWH-133 (1 mg/kg IP). Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in T1D rats. Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and T1D rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and T1D rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors (AM-630; 3 mg/kg IP). Thus, activation of CB2 receptors can potentiate reactivity of cerebral arterioles during physiologic and pathophysiologic states. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular diseases via a mechanism that can increase cerebral blood flow.

Keywords: JWH-133, reactivity, nitric oxide, ADP, NMDA, Brain

Introduction

While there is much debate as to the potential therapeutic benefits of cannabis in humans, the endocannabinoid system has been shown to have neuroprotective and neuromodulatory properties. In the brain, cannabinoids acting through both CB1 and CB2 receptors have been shown to have anti-inflammatory and neuroprotective roles in animal models of multiple sclerosis, Alzheimer’s disease, traumatic brain injury and cerebral ischemia (1, 26, 45-47). The psychotropic effects of CB1 receptors make the therapeutic use of cannabinoids limited for human subjects. However, specific activation of CB2 receptors has little or no psychotropic effects, and therefore may represent a viable therapeutic approach. CB2 receptors were first described in immune cells but also have been reported to be present on brain endothelium, neurons, astrocytes and microglia (6, 17, 25, 36). While previous studies report that activation of CB2 receptors may be neuroprotective (1, 2, 19, 47), no studies have examined whether this neuroprotection may be directed at specific components of the neurovascular unit (cerebral endothelium and/or neurons). Since the components of the neurovascular unit play an important role in the control of cerebral vascular reactivity, and hence cerebral blood flow, it is important to determine mechanisms that can influence neurovascular coupling. Thus, our first goal was to examine whether endothelial nitric oxide synthase (eNOS)- and neuronal nitric oxide synthase (nNOS)-dependent could be influenced by activation of CB2 receptors.

Type 1 diabetes (T1D) increases the risk for stroke, neurologic deficits and cognitive dysfunction (3, 5, 7, 8, 30, 32, 33). Mechanisms that account for the increased risk for stroke/neurologic deficits/reduced cognition may be related to impaired reactivity of cerebral arterioles to prevent adequate blood flow during times of increased metabolic demand, i.e., impaired neurovascular coupling. We have shown that eNOS- and nNOS-dependent responses of cerebral arterioles are altered by T1D (4, 29, 30). Although studies have identified functional alterations in the brain during T1D, no studies have examined whether activation of cannabinoid receptors can influence cerebral vascular function during T1D. Thus, the second goal of our study was to examine whether activation of CB2 receptors could influence reactivity of cerebral resistance arterioles to eNOS- and nNOS-dependent agonists during T1D. To accomplish this goal, we treated nondiabetic and diabetic rats with a specific activator of CB2 receptors (JWH-133). In addition, we examined the role of CB2 receptors by examining responses of cerebral arterioles in nondiabetic and T1D rats after treatment with JWH-133 in the presence of a specific antagonist to CB2 receptors (AM-630) (16, 39, 40).

Materials and Methods

Induction of T1D.

All procedures involving rats were reviewed and approved by the Institutional Animal Care and Use Committee at the Sanford School of Medicine, and are in accordance with the ARRIVE guidelines and the National Institutes of Health Guidelines for the Care and Use of Animals. Male Sprague-Dawley rats (200-220 grams) were divided randomly into nondiabetic and T1D groups. All rats had access to food and water ad libitum. One group of rats was injected with streptozotocin (50-60 mg/kg IP) to induce T1D. The second group of rats (nondiabetic) was injected with vehicle (sodium citrate buffer). Blood samples, for measurement of blood glucose concentration, were obtained 3-5 days after injection of streptozotocin, and on the day of the experiment.

Preparation of animals.

We followed the methods of Mayhan et al (28). Rats were prepared for studies at 12-14 weeks after injection of streptozotocin or vehicle. Rats were anesthetized (thiobutabarbital sodium; Inactin; 100 mg/kg IP), and a tracheotomy was performed. The animals were ventilated mechanically with room air and supplemental oxygen. A catheter was inserted into a femoral vein for injection of supplemental anesthesia (20-30 mg/kg, as necessary). A femoral artery was cannulated for measurement of arterial pressure, and to obtain a blood sample for the measurement of blood glucose concentration and arterial blood gases.

After these initial procedures, a craniotomy was performed over the left parietal cortex. Briefly, the rat was placed in a head holder and an incision was made in the skin to expose the skull. The skin was retracted with sutures and served as a “well” for the suffusion fluid. A cranial window was made in the bone and the dura was incised to expose the cerebral microcirculation. The cranial window was continuously suffused with a bicarbonate buffer that was bubbled with 95% nitrogen and 5% carbon dioxide. The temperature of the suffusate was maintained at 37°C. The cranial window was connected via a three-way valve to a syringe pump, which allowed for infusion of agonists into the suffusate. This method maintained a constant pH, PCO2, and pO2 of the suffusate during the infusion of agonists.

Measurement of cerebral arteriolar diameter.

The diameter of cerebral arterioles was measured using a video image-shearing monitor. Diameter of arterioles was measured immediately prior to application of agonists and at one-minute intervals during application of agonists. Application of agonists was randomized and all agonists were suffused over the cerebral microcirculation for 5 minutes. Steady-state responses were reached within 3 minutes after exposure to the agonist, and the diameter of cerebral arterioles returned to baseline within 5 minutes after application was discontinued. All agonists were prepared using the bicarbonate buffer.

Reactivity of cerebral arterioles.

The cranial window was suffused with the buffer for 30-45 min before testing responses to the agonists. In each rat, we examined responses of the largest pial arteriole exposed by the craniotomy to an eNOS-dependent agonist (adenosine-5’-diphosphate (ADP); 10 and 100 μM), an nNOS-dependent agonist (N-methyl-D-aspartate (NMDA); 30 and 100 μM), and a NOS-independent agonist (nitroglycerin; 1 and 10 μM).

In the first series of studies (JWH-133 Treated), we initially examined responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=12) and T1D (n=11) rats. Then, the rats were injected with JWH-133 (1 mg/kg IP), a specific agonist for CB2 receptors (2, 41). Sixty minutes following the injection of JWH-133, we again examined responses of arterioles to the agonists.

In the second series of experiments (JWH-133 and AM-630 Treated), we initially examined responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=6) and T1D (n=6) rats. Then, to determine the role of CB2 receptors, we injected rats with AM-630 (3 mg/kg IP). AM-630 has been shown to be a specific antagonist to CB2 receptors (16, 39, 40). Thirty minutes after the injection of AM-630, we then treated nondiabetic and T1D rats with JWH-133 (1 mg/kg IP). One hour after the injection of JWH-133, we again examined responses of arterioles to the agonists.

In a third series of experiments (Vehicle Treated), we examined a potential time-dependency in reactivity of cerebral arterioles in nondiabetic (n=8) and T1D (n=6) rats to the agonists. In these studies, we initially examined responses of arterioles to ADP, NMDA and nitroglycerin. Then, one hour after injection of vehicle (ethanol) for JWH-133 and AM-630 we again examined responses of arterioles to the agonists.

Statistical analysis.

Analysis of variance (ANOVA) with Fisher’s test for significance was used to compare reactivity of cerebral arterioles to the agonists before and following treatments with JWH-133, JWH-133/AM-630 and vehicle within and between groups of rats. Unpaired t tests were used to compare baseline diameter of cerebral arterioles, blood pressure, blood glucose concentration and body weight between nondiabetic and T1D rats. A p value of 0.05 was considered to be significant.

Results

Baseline measurements.

Baseline diameter of cerebral arterioles was similar in nondiabetic and T1D rats across all groups of rats (Table 1). In addition, treatment of the rats with JWH-133, JWH-133 and AM-630 or vehicle did not produce a change in baseline diameter in either nondiabetic or T1D rats. Mean arterial blood pressure under baseline conditions was similar in across all groups of nondiabetic and T1D rats and was not influenced by treatment with JWH-133, JWH-133 and AM-630 or vehicle (Table 1). Blood glucose concentration was significantly higher in T1D compared to nondiabetic rats across all groups of rats and body weight was lower in T1D compared to nondiabetic rats across all groups of rats (Table 1; p<0.05).

Table 1.

Nondiabetic T1D
JWH-133 Treated:
Baseline diameter (μm)
  Before JWH-133 44±2 43±2
  During JWH-133 45±3 44±2
Mean arterial pressure (mmHg)
  Before JWH-133 106±3 110±3
  During JWH-133 106±3 109±3
Blood Glucose (mg/dl) 110±4 453±14*
Body Weight (g) 383±12 303±18*
JWH-133 and AM-630 Treated:
Baseline diameter (μm)
  Before JWH-133 and AM-630 40±2 47±7
  During JWH-133 and AM-630 42±3 51±6
Mean arterial pressure (mmHg)
  Before JWH-133 and AM-630 109±3 104±1
  During JWH-133 and AM-630 106±4 112±6
Blood Glucose (mg/dl) 104±5 435±33*
Body Weight (g) 404±12 270±24*
Vehicle Treated:
Baseline diameter (μm)
  Before Vehicle 38±5 43±5
  During Vehicle 42±6 44±5
Mean arterial pressure (mmHg)
  Before Vehicle 111±4 109±6
  During Vehicle 115±5 116±7
Blood Glucose (mg/dl) 96±4 507±30*
Body Weight (g) 361±14 282±23*
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Values are means±SE.

*

p < 0.05 versus response in nondiabetic rats.

Responses in JWH-133 Treated rats.

ADP dilated cerebral arterioles in nondiabetic and T1D rats (Figure 1). However, the magnitude of vasodilation was significantly less in T1D rats compared to nondiabetic rats (Figure 1). Similarly, the magnitude of vasodilation produced by NMDA was significantly less in T1D rats when compared to nondiabetic rats (Figure 1). In contrast, nitroglycerin produced similar dose-related dilation of cerebral arterioles in nondiabetic and T1D rats (Figure 1). Thus, dilation of cerebral arterioles in response to eNOS- and nNOS-dependent, but not NOS-independent, agonists is significantly impaired by T1D. This finding is similar to what we have reported previously (4, 29, 30). Treatment with JWH-133 increased the magnitude of dilation of cerebral arterioles in response to ADP and NMDA, but not to nitroglycerin, in nondiabetic and T1D rats (Figure 1).

Figure 1.

Figure 1.

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Responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=12) and T1D (n=11) rats before and during treatment with JWH-133 (1 mg/kg IP). Values are means±SE. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response during treatment with JWH-133.

Responses in JWH-133 and AM-630 Treated rats.

ADP and NMDA dilated cerebral arterioles in nondiabetic and T1D rats (Figure 2). Again, the magnitude of vasodilation to ADP and NMDA was significantly less in T1D rats compared to nondiabetic rats (Figure 2). In contrast, nitroglycerin produced similar dose-related dilation of cerebral arterioles in nondiabetic and T1D rats (Figure 2). Treatment with AM-630 attenuated the potentiating influence of JWH-133 on eNOS- and nNOS-dependent responses of cerebral arterioles in nondiabetic and T1D rats. In addition, treatment with AM-630 did not alter responses of cerebral arterioles to nitroglycerin in nondiabetic or T1D rats (Figure 2). Thus, it appears that inhibition of CB2 receptors with AM-630 can prevent the beneficial influence of JWH-133 alone on eNOS- and nNOS-dependent responses of cerebral arterioles.

Figure 2.

Figure 2.

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Responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=6) and T1D (n=6) rats before and during treatment with AM-630 (3 mg/kg IP) and JWH-133 (1 mg/kg IP). Values are means±SE. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response in nondiabetic rats treated with AM-630 and JWH-133.

The percent difference (percent vasodilation during treatment with JWH-133 minus percent vasodilation before treatment with JWH-133) in dilation of cerebral arterioles produced by JWH-133 was larger in T1D rats than in nondiabetic rats for the high dose of ADP and for both doses of NMDA (Figure 3). However, treatment with AM-630 significantly attenuated the potentiation of vasodilation in response to JWH-133 (Figure 3). The percent change in response to nitroglycerin was not influenced by treatment with JWH-133 in the absence or presence of AM-630.

Figure 3.

Figure 3.

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Percent difference in response of cerebral arterioles to ADP and NMDA during treatment with JWH-133 or during treatment with JWH-133/AM-630 in nondiabetic (n=12) and T1D (n=11) rats. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response in nondiabetic and T1D rats during treatment with JWH-133.

Responses in Vehicle Treated rats.

To assure that there were no time-dependent influences on reactivity of cerebral arterioles to the agonists during treatment with JWH-133 and/or AM-630, we examined responses following treatment with vehicle (ethanol). We found that responses to ADP and NMDA were not influenced by a time-dependent phenomenon in nondiabetic and T1D rats. That is, responses to ADP and NMDA were similar before and following treatment with vehicle in nondiabetic and T1D rats, and responses of arterioles to ADP and NMDA were significantly less in T1D compared to nondiabetic rats (Figure 4). In addition, nitroglycerin produced similar dose-related dilation of cerebral arterioles in nondiabetic and T1D rats (Figure 4) and this also was not influenced by a time-dependent phenomenon (Figure 4).

Figure 4.

Figure 4.

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Responses of cerebral arterioles to ADP, NMDA and nitroglycerin in nondiabetic (n=8) and T1D (n=6) rats before and after treatment with vehicle. Values are means±SE. * p < 0.05 versus response in nondiabetic rats. ** p < 0.05 versus response in nondiabetic rats treated with vehicle.

Discussion

There are four new findings of the present study. First, we found that JWH-133, a specific agonist of CB2 receptors, could potentiate eNOS- and nNOS-dependent responses of cerebral arterioles in nondiabetic rats. Second, we found that acute treatment with JWH-133 could rescue impaired eNOS- and nNOS-dependent responses of cerebral arterioles during T1D. Third, we found that inhibition of CB2 receptors with AM-630 could prevent the potentiating influence of JWH-133 on reactivity of cerebral arterioles in nondiabetic and T1D rats. Fourth, we found that the findings from this study regarding reactivity of cerebral arterioles could not be explained by a time-dependent effect. We speculate that treatment with agonists of the CB2 receptor may be a potential therapeutic approach to improve cerebral perfusion, especially during disease states that predispose the brain to ischemic damage.

We used ADP as our eNOS-dependent agonist, NMDA as our nNOS-dependent agonist, and nitroglycerin as our NOS-independent agonist. ADP binds to purinergic G-protein-coupled receptors (P2y) (22, 44) and appears to dilate cerebral arterioles through a pathway involving activation of eNOS (12, 31,44). While some (11) have suggested that dilation of cerebral arterioles in response to ADP may be related to the release of endothelium-derived hyperpolarizing factor (EDHF) through activation of potassium channels, others (9) have shown that potassium channel activation does not have a significant role in dilation of cerebral arterioles to ADP. In the case of NMDA, it has been shown that NMDA dilates cerebral arterioles through a pathway involving nNOS (10, 13, 14). Thus, it appears that ADP and NMDA are appropriate agonists to examine eNOS- and nNOS-dependent dilation in cerebral arterioles.

The marijuana plant, Cannabis, has been used for psychotropic and medicinal purposes for hundreds, if not thousands, of years. Cannabinoids, the synthetic analogs of cannabis, have been reported to have neuroprotective properties in animal models of multiple sclerosis, Alzheimer’s disease, traumatic brain injury and cerebral ischemia (1, 26, 45-47). Mechanisms that account for the neuroprotective role of cannabinoids are not entirely clear but may relate to inhibition of oxidative stress (16), downregulation of inflammatory mediators (15, 40), inhibition of leukocyte adhesion to the endothelium (38, 45, 47) and/or activation of PPAR’s (18, 35).

In addition to examining the neuroprotective influence of cannabinoids, studies have examined the influence of activation of cannabinoid receptors on vascular function. Labota et al (24) found that relaxation of mesenteric arteries to the endocannabinoid, anandamide, is reduced in Zucker obese rats. These authors (24) suggested that the alteration in response to anandamide was related to a decrease in receptor expression, an increase in anandamide degradation, and/or a decrease in eNOS activity. Wheal et al (43) reported that impaired eNOS-dependent relaxation of the femoral artery in Zucker obese rats could be improved by acute (2 hours) treatment with cannabidiol (a non-specific activator of CB1 and CB2 receptors). The mechanism for this influence of cannabidiol on vascular function appeared to be related to production of vasodilator agents via the cyclooxygenase pathway (43). Finally, Vella et al (42) found that chronic treatment of T1D rats with a nonspecific activator of cannabinoid receptors (THC) could prevent impaired eNOS-dependent responses of the thoracic aorta and mesenteric arteries. The mechanism for the protective influence of THC in T1D rats appeared to be related to an alteration in blood glucose concentration and/or a decrease in oxidative stress (42). These authors (42) did not report a significant effect of activation of cannabinoid receptors on vascular responses in nondiabetic rats. In the present study, we found that treatment of rats with a specific agonist of CB2 receptors could augment eNOS- and nNOS-dependent dilation of cerebral arterioles in both nondiabetic and T1D rats. These findings complement and extend the findings of others by examining responses of resistance arterioles in the brain, vessels that directly determine tissue blood flow, and by examining the specific role for activation of CB2 receptors in T1D-induced impairment in cerebral vascular function.

We also examined the role of CB2 receptors in potentiation of cerebral vascular function by JWH-133 by treating rats with a selective and competitive antagonist of CB2 receptors, AM-630 (16, 39, 40). These previous studies found that AM-630 could prevent the protective influence of activation of CB2 receptors with JWH-133 or cannabigerol in cell and animal models. We found that treatment with AM-630 prevented the potentiation in responses of cerebral arterioles to eNOS- and nNOS-dependent agonists, but not to a NOS-independent agonist. This suggests that treatment with JWH-133 does not potentiate cerebral vascular function via a nonspecific effect but must act via stimulation of CB2 receptors. In addition, we determined that there was no time-dependency in responses of cerebral arterioles to the agonists used in the present study. Thus, the effects of JWH-133 on cerebral vascular function cannot be explained by an effect of repeated application of agonists to cerebral arterioles.

The mechanism(s) that contribute to potentiation of cerebral vascular function by JWH-133 in nondiabetic and T1D rats is not clear from the present study. We considered the possibility that acute treatment with JWH-133 might act by decreasing oxidative stress. We have shown in previous studies that T1D increases oxidative stress and that this increase in oxidative stress contributes to impaired responses of cerebral arterioles during T1D (4, 27). However, inhibition of oxidative stress did not influence cerebral vascular function in nondiabetic rats. Thus, while it is possible that JWH-133 may influence oxidative stress in T1D rats, it appears unlikely that JWH-133 would improve cerebral vascular function in nondiabetic rats via an effect on oxidative stress. Others have shown that cannabinoids may be protective via activation of PPARs (18, 35). Several studies have shown that activation of PPARs can restore vascular dysfunction, brain injury and cognitive impairment during diabetes (20, 21, 23, 34, 37). Thus, it is conceivable that JWH-133 may act via stimulation of PPARs in cerebral arterioles. It is also possible that treatment with JWH-133 may be directly influencing eNOS and nNOS protein leading to an increase in nitric oxide release in response to ADP and NMDA. Since we did not precisely determine the role of nitric oxide in responses of cerebral arterioles following treatment with JWH-133 we cannot rule out this possibility. Others have shown that treatment with JWH-133 can prevent blood-brain barrier dysfunction and cognitive impairment in via inhibition in the expression of inflammatory mediators (38, 40). It is possible that potentiation of cerebral vascular function in nondiabetic and T1D rats may be related to inhibition in the synthesis/release of inflammatory mediators. Additional studies will be necessary to determine the precise mechanism(s) responsible for augmented cerebral vascular function by treatment with JWH-133. In addition, a potential limitation of the present study is that we examined responses of cerebral arterioles in young male nondiabetic and T1D rats, future studies will need to include older animals and female animals.

In summary, we found that acute treatment with a specific activator of CB2 receptors could potentiate dilation of cerebral resistance arterioles to eNOS- and nNOS-dependent agonists in both nondiabetic and T1D rats. In addition, the influence of activation of CB2 receptors on cerebral vascular function could be attenuated by treatment with a specific antagonist of CB2 receptors (AM-630). We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular disease that can contribute to the pathogenesis of stroke.

Highlights:

  • CB2 receptors and cerebral vascular function.

  • Activation of CB2 receptors improves cerebral vascular function.

  • Activation of CB2 receptors improves responses in type 1 diabetes.

  • Inhibition of CB2 receptors prevents improvement in vascular function.

Acknowledgments

This study was supported by a grant from the Diabetes Research and Action Education Foundation, NIH AA027206, a Summer Medical Student Fellowship awarded to Lauren Van Hove and funds from the Sanford School of Medicine at the University of South Dakota.

Footnotes

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