Upper airway microcirculation remodeling in obstructive sleep apnea is not driven by endothelial activation

Abstract

Microcirculation contributes significantly to blood flow resistance, with upper airway microcirculation in obstructive sleep apnea (OSA) affected by endothelial activation, perturbed blood flow shear stress, and snoring-induced tissue vibration. The relevance of these mechanisms on microcirculation response and remodeling remains largely unknown but may influence management decisions in OSA. This study analyzed pharyngeal muscle tissue from non-obese, young adult patients with OSA and chronic heavy snoring. We assessed arteriole morphometry and quantified the expression of endothelial activation markers: 8-isoprostane, vascular cell adhesion molecule-1, E-selectin, vascular endothelial growth factor, endothelin-1, and endothelial cell specific molecule-1. Morphometric analysis of 319 arterioles (mean of 8 vessels per patient) revealed thicker walls in severe OSA compared to mild OSA without lumen reduction, indicating outward hypertrophy, and a positive correlation between the apnea-hypopnea index (a measure of OSA severity) and arteriole wall thickness. However, analysis of 1872 arterioles showed no increase in endothelial activation markers with disease severity, either in the arteriole walls or muscle tissue. This suggests that, in young non-obese adults, severe OSA likely leads to adaptive, mechanically driven microcirculation outward hypertrophy, potentially due to perturbed shear stress, with potential implications for OSA management.

Keywords: Endothelial dysfunction; Microcirculation; Obstructive sleep apnea; Outward hypertrophy; Remodeling; Upper airway.

Fig. 1

Illustrative case of immunohistochemical expression (brown staining) of endothelial activation markers in the microcirculation. All images from a male patient, 23 years-old, with an apnea–hypopnea index of 33.4 events/h. Markers: 8-isoprostane (A), vascular cell adhesion molecule 1, VCAM-1 (B), E-selectin (C), vascular endothelial growth factor, VEGF (D), endothelin 1, ET-1 (E), endothelial cell specific molecule 1, ESM-1 (F). Scale bar: 100 µm, 20× magnification. V, vessel.

Fig. 2

Illustrative case of immunohistochemical expression (brown staining) with Endothelial cell specific molecule-1 (ESM-1) in severe OSA. Microcirculation marked with ESM-1 before (A) and after (B) imaging processing. For each vessel, we calculated the integrated optical density (marked in red in panel B, black arrow) normalized by the outer perimeter (scale bar: 100 µm, 20× magnification).

Fig. 3

Illustrative case of immunohistochemical expression (brown staining) with Endothelial cell specific molecule-1 (ESM-1) in severe OSA. Pharyngeal muscle marked with ESM-1 before (A) and after (B) imaging processing. Area of interest of the muscle is outlined in green and integrated optical density is marked in red, normalized by the measured area (scale bar: 100 µm, 10× magnification).

Fig. 4

Pharyngeal muscle microcirculation wall thickness among the OSA severity groups. Dunn’s post hoc test.

Fig. 5

Illustrative cases of microcirculation wall thickness (white arrows) in pharyngeal muscles in mild (A), moderate (B) and severe (C) OSA. Verhoeef Masson staining. Elastic tissue in black, muscle tissue in red and connective tissue in blue (scale bar: 100 µm, 20× magnification).

Fig. 6

Correlation between apnea–hypopnea index (AHI) and pharyngeal muscle microcirculation wall thickness in patients with OSA. Spearman’s correlation test.