Celentano, Camilla (2025) Kv7 CHANNELS AS NOVEL REGULATORS OF BLOOD-BRAIN BARRIER FUNCTION AND DYSFUNCTION. [Tesi di dottorato]

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Abstract

Positioned at the interface between the blood and the central nervous system (CNS), the blood-brain barrier (BBB) is a critical regulator of brain homeostasis and neuronal function. The BBB is primarily comprised of brain microvascular endothelial cells (BMECs) sealed by tight junction proteins (TJs), such as Zonula-Occludens 1 (ZO1), claudin-5, and occludin, which strictly regulate paracellular permeability. Furthermore, the transcellular flux of solutes and ions is selectively regulated by transporters and ion channels that also affect ionic homeostasis, cerebral blood flow, and BMEC proliferation, and can have a role in microvascular dysfunction, which is associated with several diseases, such as epilepsy or stroke. In addition, accumulating evidence suggests that the renin-angiotensin system (RAS) is altered during epilepsy and affects BBB permeability. Among the ion channels expressed in the CNS, the voltage-gated Kv7 potassium channel family, that encompasses five members (Kv7.1–5), play a major role in controlling the function of excitable and non-excitable cells. In particular, Kv7.2, Kv7.3, and Kv7.5 participate in the regulation of neuronal excitability, and mutations in these genes are associated with forms of epilepsy showing different degrees of severity. In the present study, we aimed to assess the expression and the pathophysiological role of voltage-gated Kv7 potassium channels within the BBB. The findings revealed that Kv7.1, Kv7.4, and Kv7.5 are expressed in BMECs, where they function as critical modulators of barrier permeability under physiological conditions and in experimental models of epilepsy. Notably, Kv7.5 channels, characterized by a distinct peripheral distribution in BMECs, localized at cell-to-cell junction sites, were selectively downregulated in brain microvessels (BMVs) isolated from epileptic rats (Kainic-acid induced status epileptic rats). Moreover, Kv7.5 homozygous knockout rats demonstrated increased baseline BBB permeability, altered ZO1 protein expression and heightened seizure susceptibility. Finally, we observed that the Kv7 activators retigabine and ML213 mitigated the reduction in BBB integrity induced by Ang II, potentially by reducing the redistribution of ZO-1 from TJs through mechanisms involving phosphorylation and alterations in calcium levels. Overall, these findings demonstrate that Kv7 channels are expressed in the BBB, where they modulate barrier properties in both physiological and pathological conditions. Furthermore, this study underscores the role of Kv7.5 channels in influencing BBB integrity and seizure susceptibility, highlighting their potential as therapeutic targets for epilepsy and other neurological disorders.

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