Increases in Plasma Viscosity Disrupt Microvascular Flow Dynamics

Background: Autoregulation of blood flow depends on pressure induced constriction and flow mediated dilation. These processes are well defined in arterioles, but how blood enters and distributes within the capillary network, the primary site of oxygen and nutrient exchange, is less understood. Endothelial cells and pericytes are increasingly recognized as active regulators of capillary tone, yet the mechanisms governing capillary level autoregulation remain unclear. Plasma viscosity is a major determinant of shear stress and may influence this regulation, but its role is not fully defined. Methods: Using an ex vivo pressurized retinal preparation that preserves the arteriole to capillary continuum, we examined how changes in intraluminal viscosity and shear stress affect endothelial and mural cell activity during pressure driven flow. To study chronic viscosity elevation, we assessed microvascular structure, remodeling, endothelial responsiveness, and capillary perfusion in a high fat diet model of altered blood rheology. Results: Increasing viscosity enhanced endothelial Ca2+ activity in transitional and capillary segments and suppressed pressure induced Ca2+ elevations in smooth muscle cells and pericytes through nitric oxide dependent inhibition. Chronic elevation of viscosity produced segment specific effects. Arterioles showed structural remodeling and higher tone, whereas transitional and capillary vessels did not remodel and instead exhibited impaired endothelial shear sensing and reduced capillary recruitment. High fat diet feeding lowered baseline capillary perfusion and eliminated viscosity dependent modulation, indicating loss of shear-based control. Conclusions: Autoregulation differs fundamentally between arterioles and capillaries, and viscosity dependent endothelial signaling is a key determinant of capillary entry and flow distribution. Plasma viscosity is an important regulator of microvascular perfusion and a potential biomarker and therapeutic target in microvascular disease. Key Words: capillary autoregulation; plasma viscosity; endothelial shear sensing