Chronic hypoxia and the carotid body: the role of CD73 in carotid body hyperactivity and cardio-respiratory function

Nathanael, Demitris ORCID: 0000-0002-1811-5960 (2025). Chronic hypoxia and the carotid body: the role of CD73 in carotid body hyperactivity and cardio-respiratory function. University of Birmingham. Ph.D.

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Abstract

Carotid body hyperactivity is increasingly recognised as a major contributor to neurogenic hypertension, particularly in cardiovascular-respiratory related diseases including chronic obstructive pulmonary disease (COPD). In COPD, chronic hypoxia persistently excites the carotid body, driving excessive sympathetic outflow contributing to hypertension. However, the mechanisms underlying carotid body hyperactivity remain unclear. CD73, an ecto-nucleotidase, plays a crucial role in setting basal carotid body activity and hypoxic sensitivity. Whether CD73 contributes to chronic hypoxia-induced carotid body hyperactivity is unknown. This thesis initially characterised and validated a chronic hypoxia model in rats using 10 days exposure to 12% FiO2. Experiments subsequently investigated alterations in the cellular distribution of CD73 in the carotid body in response to chronic hypoxia and the functional importance of CD73 in promoting chemoafferent hyperexcitability. Final experiments examined whether in vivo pharmacological targeting of CD73 produced beneficial cardiovascular alterations in chronically hypoxic animals. Chronic hypoxia increased the number of CD73+TH+ cells within the carotid body. Pharmacological inhibition of CD73 abolished chronic hypoxia-induced basal chemoafferent hyperactivity and normalised heightened hypoxic sensitivity ex vivo. CD73 antagonism in vivo reduced blood pressure in a carotid body-dependent manner while preserving cardiovascular-respiratory reflexes during hypoxia. This research suggests that CD73 is an important modulator of carotid body hyperactivity in chronic hypoxia. The work highlights a potential new strategy for reducing carotid body hyperactivity and blood pressure without impairing hypoxia responsiveness. These findings should promote the development of carotid body/CD73-targeted treatments for chronic hypoxia-related conditions such as COPD.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):