Junctions, Transporters, and Interactions of Endothelial Cells: Regulation by Ethanol

Alcohol (ethanol, an intoxicating agent in all alcoholic beverages) is the most widely consumed beverage in the United States and is a leading risk-factor for cerebrovascular diseases. Although neurons, microglia, and astrocytes have been moderately studied for their responsiveness to ethanol, the brain vasculature is minimally explored and is emerging as a key player in the interplay between neuroinflammation, cerebrovascular disease, and alcohol use disorder (AUD). The blood-brain barrier (BBB), a critical regulator of brain homeostasis, relies on the coordinated function of various cellular and molecular components to maintain its immune-privileged status. Emerging evidence indicates that chronic ethanol exposure disrupts BBB function, contributes to neurovascular dysfunction, and increases brain permeability to peripheral immune factors. This review introduces the endothelial cells (ECs) that make up the BBB and provides a brief overview of the junction proteins and transporters that assist with EC function and EC interactions with other cells of the neurovascular unit, including pericytes, smooth muscle cells, and perivascular macrophages and glial cells. In addition, this review highlights ethanol's effects on ECs and the cells that interact with them. Lastly, given the mounting evidence on gender differences in AUD and the supporting sex differences in ethanol consumption in preclinical models, this review discusses the discovered sex differences in EC-specific genes and identifies open questions such as the influence of sex-dependent differences, genetic factors, and their interactions with ethanol on EC function. Taken together, a deeper understanding of how ethanol disrupts EC structure and function will advance therapeutic strategies to mitigate neuroinflammation and related pathologies associated with chronic ethanol exposure.