Ibec Seminar. Fidel Lolo Romero and Miguel Angel del Pozo
Decoding the Mechanics of Brain Endothelium: CAV1-Dependent Invaginations as modulators of neurovascular coupling
Fidel Lolo Romero
Endothelial cells of the brain vasculature are continuously exposed to mechanical forces that regulate essential functions including endocytosis, barrier integrity, and neurovascular coupling (NVC). Plasma membrane (PM) tension serves as a critical mechanotransductive cue, and specialized PM invaginations—such as caveolae—buffer abrupt mechanical stress in arteriolar endothelial cells, where shear forces and blood flow are high. Notably, capillary endothelial cells, which experience lower mechanical load, lack morphologically detectable caveolae yet express Caveolin-1 (CAV1), the principal structural component of caveolae. Recent findings from our lab (Lolo et al., Nat. Cell Biol. 2023) have identified a novel class of CAV1-dependent invaginations, termed dolines, which form independently of caveolae and respond to subtle shifts in PM tension—suggesting a new mechanoadaptive role for CAV1 in capillaries. Building on this discovery, our research aims to dissect the distribution, regulation, and functional implications of CAV1-based structures across the cerebrovascular network. We combine advanced in vitro systems with in vivo behavioral analyses to: (i) map the spatial distribution of dolines and other CAV1-dependent structures across the brain endothelium; (ii) investigate how lipid composition modulates their biogenesis and stability; (iii) determine how phosphorylation at tyrosine-14 (Y14)—a key post-translational modification of CAV1—affects membrane tension sensing and nanoparticle internalization; (iv) evaluate how neuronal activity dynamically regulates CAV1 structures during neurovascular signaling; and (v) assess the downstream behavioral consequences of modulating these mechanosensitive pathways in animal models. We will present preliminary findings elucidating the role of endothelial CAV1 in neurovascular coupling, providing new insights that may advance our understanding of complex brain functions such as memory consolidation.
