Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors

Simon Lambden,Andrew S Cowburn,Randall S Johnson,Tessa A C Garrud,Bernardo J Krause,Dino A Giussani,Charlotte Summers,David Macias

doi:10.1186/s40635-021-00390-y

Abstract

BackgroundThe vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α. In vivo, arterial blood pressure and metabolic activity were monitored continuously in normal atmospheric conditions and following an acute stimulus with hypoxia (10%) or lipopolysaccharide (LPS). Ex vivo, femoral artery reactivity was assessed using wire myography.ResultsUnder normoxia, the HIF-1α Tie2Cre mouse had increased systolic and diastolic arterial pressure compared to litter mate controls over the day–night cycle under normal environmental conditions. VO2 and VCO2 were also increased. Femoral arteries displayed impaired endothelial relaxation in response to acetylcholine mediated by a reduction in the nitric oxide dependent portion of the response. HIF-1α L1Cre mice displayed a similar pattern of increased systemic blood pressure, metabolic rate and impaired vascular relaxation without features of pulmonary hypertension, polycythaemia or renal dysfunction under normal conditions. In response to acute hypoxia, deficiency of HIF-1α was associated with faster resolution of hypoxia-induced haemodynamic and metabolic compromise. In addition, systemic haemodynamics were less compromised by LPS treatment.ConclusionsThese data show that deficiency of HIF-1α in the systemic or pulmonary endothelium is associated with increased systemic blood pressure and metabolic rate, a pattern that persists in both normoxic conditions and in response to acute stress with potential implications for our understanding of the pathophysiology of vascular dysfunction in acute and chronic disease.

Highlights

The vascular endothelial cell has a central role in the cardiovascular system, and as such participates in the pathophysiology of multiple cardiovascular diseases [1, 2]
Hypoxia-inducible factor (HIF)-1α Tie2 Cre deletion was associated with significantly elevated mean ± SEM oxygen consumption compared to litter mate controls (3368 ± 62 mL/min/m2 vs 2804 ± 58 mL/min/m2, p = 0.019, Fig. 1e) with a similar pattern of CO2 production observed (2933 ± 75 mL/min/m2 vs 2458 ± 62 mL/min/m2, p = 0.038, Fig. 1f )
We show that loss of HIF-1α in the vascular endothelium results in a significant increase in systemic metabolic activity, blood pressure, and change in vascular function under normoxic conditions—a pattern persistent in two different models of acute stress suggesting that it may be a physiologically relevant process that merits further exploration

Summary

Introduction

The vascular endothelial cell has a central role in the cardiovascular system, and as such participates in the pathophysiology of multiple cardiovascular diseases [1, 2]. The endothelium contributes extensively to the regulation of vascular tone, permeability and blood flow through both direct synthesis of mediators such as nitric oxide and indirectly by regulating circulating vasoactive substances such as catecholamines and angiotensin II [3] Dysregulation of these pathways has been associated with the development of both acute and chronic vascular dysfunction [4] and in critical illness, impaired endothelial function has been widely reported and associated with poor outcomes [5–9]. There is evidence that HIF stabilisation can be driven by other stimuli, including inflammation [10, 11] and, in vascular endothelial cells, shear stress [12] These alternate pathways of HIF regulation may, for example, act in the progression of atherosclerosis [12] suggesting that a functional role for the HIF isoforms in both homeostatic and stress-induced conditions other than hypoxia is possible. Femoral artery reactivity was assessed using wire myography

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