Manipulating the endocannabinoid system to alter cardiovascular function in hypertension

Hypertension describes a condition of high blood pressure. Aptly dubbed the ‘Silent Killer’, it has no obvious outward symptoms but is a major risk factor for cardiovascular pathologies such as stroke, heart failure and coronary heart disease. There is a clear need for therapies that lower blood pressure and diminish hypertension-related morbidity and mortality. One mechanism driving high blood pressure is the overactivation of our sympathetic nervous system. Critically, overactivation of our sympathetic nervous system confers damage to cardiovascular tissue independently of its effect on blood pressure. This represents the following rationale: Interventions that normalise sympathetic nerve activity have the potential to lower blood pressure and mitigate cardiovascular damage beyond reductions in blood pressure. It is unclear why sympathetic activation of blood vessels is elevated in hypertension. One proposed mechanism is the failure of regulatory mechanisms that apply a ‘brake’ to sympathetic activity. Sensory and nitrergic nerves, as well as our endogenous cannabinoid system, are thought to dampen sympathetic nerve-mediated activation in cardiovascular tissue. Yet, there are no anti-hypertensive therapies that target the endocannabinoid system, mostly because we do not have sufficient understanding of how the system interacts and cross-regulates with the sympathetic nervous system in cardiovascular tissue. This project will use techniques to assess cardiac and vascular function ex vivo in an experimental model of hypertension to investigate the effect of endogenous cannabinoids on nerve-mediated responses in the cardiovascular system. The student will also assess structural changes in cardiovascular tissue using a combination of histology, morphometry and stereology.

(Hypertension describes a condition of high blood pressure. Aptly dubbed the ‘Silent Killer’, it has no obvious outward symptoms but is a major risk factor for cardiovascular pathologies such as stroke, heart failure and coronary heart disease. There is a clear need for therapies that lower blood pressure and diminish hypertension-related morbidity and mortality.

One mechanism driving high blood pressure is the overactivation of our sympathetic nervous system. Critically, overactivation of our sympathetic nervous system confers damage to cardiovascular tissue independently of its effect on blood pressure. This represents the following rationale: Interventions that normalise sympathetic nerve activity have the potential to lower blood pressure and mitigate cardiovascular damage beyond reductions in blood pressure. It is unclear why sympathetic activation of blood vessels is elevated in hypertension.

One proposed mechanism is the failure of regulatory mechanisms that apply a ‘brake’ to sympathetic activity. Sensory and nitrergic nerves, as well as our endogenous cannabinoid system, are thought to dampen sympathetic nerve-mediated activation in cardiovascular tissue. Yet, there are no anti-hypertensive therapies that target the endocannabinoid system, mostly because we do not have sufficient understanding of how the system interacts and cross-regulates with the sympathetic nervous system in cardiovascular tissue.

This project will use techniques to assess cardiac and vascular function ex vivo in an experimental model of hypertension to investigate the effect of endogenous cannabinoids on nerve-mediated responses in the cardiovascular system. The student will also assess structural changes in cardiovascular tissue using a combination of histology, morphometry and stereology.

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