High intraluminal pressure promotes vascular inflammation via caveolin-1

Robert G Parton,Waled A Shihata,Danielle L Michell,Ann-Maree Jefferis,Amanda K Sampson,Jaye P F Chin-Dusting,Karen L Andrews,Kevin J Woollard,Marie-Odile Parat,Natalie G Lumsden,Nurul Aisha Zainal Abidin,Olivier Huet,David M Kaye,Garry L Jennings,Andrew J Murphy

doi:10.1038/s41598-021-85476-z

Abstract

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. Recent data suggest that vascular inflammation may also play a key role in the pathogenesis of hypertension. This study sought to determine whether high intraluminal pressure results in vascular inflammation. Leukocyte adhesion was assessed in rat carotid arteries exposed to 1 h of high intraluminal pressure. The effect of intraluminal pressure on signaling mechanisms including reactive oxygen species production (ROS), arginase expression, and NFĸB translocation was monitored. 1 h exposure to high intraluminal pressure (120 mmHg) resulted in increased leukocyte adhesion and inflammatory gene expression in rat carotid arteries. High intraluminal pressure also resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation. This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)-deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Cav1 deficiency also resulted in a reduction in pressure-induced glomerular macrophage infiltration in vivo. These findings demonstrate Cav1 is an important mechanosensor in pressure-induced vascular and renal inflammation.

Highlights

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction
We discovered that leukocyte adhesion over a 10 min perfusion period at physiological sheer stress, was significantly increased in rate carotid artery (RCA) segments pressurised for 1 h at 120 mmHg compared to segments pressurised at low (60 mmHg) and normotensive (80 mmHg) conditions (Fig. 1A-B)
Consistent with the enhanced leukocyte adhesion, we observed a significant increase in mRNA expression of endothelial adhesion molecules in arteries pressurised at 120 mmHg compared to unpressurised vessels (Fig. 1C-D)

Summary

Introduction

The aetiology and progression of hypertension involves various endogenous systems, such as the renin angiotensin system, the sympathetic nervous system, and endothelial dysfunction. High intraluminal pressure resulted in a downstream signaling cascade of ROS production, arginase expression, and NFĸB translocation This process was found to be angiotensin II-independent and mediated by the mechanosensor caveolae, as caveolin-1 (Cav1)deficient endothelial cells and mice were protected from pressure-induced vascular inflammatory signaling and leukocyte adhesion. Vascular endothelial and smooth muscle cell inflammation is a complex and dynamic process involving expression and activation of adhesion molecules, reactive oxygen species (ROS) and innate and adaptive immune cell recruitment and infiltration into these tissues. In experimental hypertension models, enhanced expression of adhesion molecules including ICAM-1 and P-selectin has been observed upon stimulation of nuclear factor κB (NF-κB)[11] Together these pathways aid in the recruitment and adhesion of the immune cells involved in hypertensive-related vascular pathologies. Understanding the relevance of high intravascular pressure will provide insights on why maintenance of normal blood pressure in those with hypertension is important to prevent hypertension-associated end organ damage

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