Diverging Roles of Inflammation, Glycocalyx Degradation, and Nitric Oxide Signaling in the Coordination of Microvascular Perfusion

Abstract

ObjectiveNumerous studies have reported changes in microvascular perfusion related to inflammation, endothelial glycocalyx degradation, and/or nitric oxide (NO) signaling. Perfusion is increased by NO signaling, reduced by inflammation, and is more heterogeneous under conditions of inflammation. It is unknown whether changes in flow distribution or perfused capillary density occur independently of, or due to, changes in capillary velocity.MethodsStudies were performed on the lateral gastrocnemius of anesthetized mice. Capillaries were visualized using a rhodamine‐labelled 2‐Megadalton dextran, and perfusion was measured in ~600 capillaries per mouse using custom image analysis software. Perfusion states were compared (n=8/group) 45 minutes after delivery of: 1) 0.9% saline 100 μl injection, 2) hyaluronidase (60 units) injection to degrade the glycocalyx, and 3) continuous infusion (37 μg/kg/min) sodium nitroprusside (SNP), an NO donor. An addition group was studied 2 h after lipopolysaccharide (LPS; 2μg/g) injection. Groups were compared for differences in mean capillary flow velocity (MFV), a perfusion heterogeneity index (PHI), proportion of vessels with flowing blood (PPV), and the relationships between these perfusion parameters.ResultsBaseline MFV was 367±36 μm/s (mean±SE for all groups). Hyaluronidase increased MFV to 511±45 μm/s (p<0.05), while LPS decreased MFV to 184±23 μm/s (p<0.01) and SNP increased it to 558±32 μm/s (p<0.01). Baseline PHI was 1.05±0.03. LPS increased PHI to 1.33±0.04 (p<0.0001) while SNP decreased it to 0.85±0.01 (p<0.0001). Hyaluronidase did not significantly alter PHI or PPV (p=NS), but it did alter the relationships between MFV and other perfusion parameters. PPV was related to MFV by an asymptotic curve, and PPV at a given MFV was significantly decreased by both LPS (p<0.05) and hyaluronidase (p<0.01). This regression predicted observed PPV with R2=0.96, p<0.0001. PHI was linearly related to the inverse of the square root of MFV, and PHI at a given MFV was significantly decreased by SNP (p<0.01) and increased by LPS (p<0.05). This regression predicted observed PHI with R2=0.87, p<0.0001.ConclusionsIncreases in capillary flow velocity are associated with increases in the proportion of perfused vessels and decreases in perfusion heterogeneity, suggesting a potential role for bulk perfusion in determining flow distribution. The curves relating flow velocity to capillary perfusion can be acutely shifted by endothelium‐altering stimuli such as endothelium glycocalyx degradation and inflammation (which decrease capillary perfusion independently of flow) or enhanced nitric oxide delivery (which homogenizes perfusion independently of flow).Support or Funding InformationThis study was funded by NIH Grants DK059637 and DK054902, and the American Heart Association SFRN at VanderbiltThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.