Blood–Brain Barrier and Its Overlooked Proteoglycan Regulators

The blood–brain barrier (BBB), together with associated perivascular cells, forms a key component of the neurovascular unit and constitutes a highly specialized multicellular interface that tightly regulates the movement of ions, nutrients, oxygen, metabolites, and immune cells between the circulation and the central nervous system (CNS). This selective barrier is essential for maintaining CNS homeostasis, supporting neuronal function, and protecting neural tissue from circulating toxins, pathogens, and inflammatory mediators. Disruption of BBB integrity is a hallmark of numerous neurological disorders and contributes to disease initiation and progression. Among the structural components of the BBB, the endothelial glycocalyx has emerged as a critical yet underrecognized regulator of barrier function. This carbohydrate-rich layer, composed primarily of proteoglycans, glycoproteins, and glycolipids, forms an important interface between circulating blood and the brain endothelium. Beyond serving as a physical barrier, glycocalyx proteoglycans regulate vascular permeability, mechanotransduction, leukocyte adhesion, and inflammatory signaling, thereby contributing to BBB integrity and cerebrovascular homeostasis. In this review, we discuss the architecture and function of the BBB, highlight the overlooked roles of proteoglycans in maintaining BBB integrity and regulating neurovascular function, examine their contributions to BBB dysfunction in neurological diseases, and explore emerging therapeutic approaches targeting the glycocalyx to preserve or restore BBB integrity.