How big is the endothelium? Comment on “Spatial and temporal dynamics of the endothelium”

Rajala, Rahul

doi:10.1111/jth.15469

Cited by 4 publications

(3 citation statements)

References 2 publications

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“…The luminal surface is coated with the endothelial glycocalyx, a gel-like matrix of proteoglycans and glycoproteins [ 8 ]. In humans, estimates of endothelial surface area vary between 270 and 7000 m 2 [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Vascular leak in sepsis: physiological basis and potential therapeutic advances

McMullan,

McAuley,

O’Kane

et al. 2024

Crit Care

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Sepsis is a life-threatening condition characterised by endothelial barrier dysfunction and impairment of normal microcirculatory function, resulting in a state of hypoperfusion and tissue oedema. No specific pharmacological therapies are currently used to attenuate microvascular injury. Given the prominent role of endothelial breakdown and microcirculatory dysfunction in sepsis, there is a need for effective strategies to protect the endothelium. In this review we will discuss key mechanisms and putative therapeutic agents relevant to endothelial barrier function.

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Section: Introductionmentioning

confidence: 99%

Vascular leak in sepsis: physiological basis and potential therapeutic advances

McMullan,

McAuley,

O’Kane

et al. 2024

Crit Care

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“…The vascular endothelium, which forms the inner lining of blood vessels, is a sprawling cell layer covering a total surface area of 270–720 square meters 1 . Endothelial cells (ECs) participate in the regulation of tissue function and structure, the trafficking of hormones and nutrients 2 , the control of inflammation 3 , and the regulation of vascular permeability 4 .…”

Section: Introductionmentioning

confidence: 99%

Acetaminophen Overdose Reveals Protease-Activated Receptor 4 as a Low-Expressing but Potent Receptor on the Hepatic Endothelium

Rajala,

Cleuren,

Griffin

2024

Preprint

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Background & AimsHepatic endothelial cell (EC) dysfunction and centrilobular hepatocyte necrosis occur with acetaminophen (APAP) overdose. The protease thrombin, which is acutely generated during APAP overdose, can signal through protease-activated receptors 1 and 4 (PAR1/PAR4). PAR1 is a high-affinity thrombin receptor that is known to signal on ECs, whereas PAR4 is a low-affinity thrombin receptor, and evidence for its expression and function on ECs is mixed. This study aims to exploit the high levels of thrombin generated during APAP overdose to determine (1) if hepatic endothelial PAR4 is a functional receptor, and (2) endothelial-specific functions for PAR1 and PAR4 in a high thrombin setting.MethodsWe generated mice with conditional deletion(s) ofPar1/Par4in ECs and overdosed them with APAP. Hepatic vascular permeability, erythrocyte congestion/bleeding, and liver function were assessed following overdose. Additionally, we investigated the expression levels of endothelial PARs and how they influence transcription in APAP-overdosed liver ECs using endothelial Translating Ribosome Affinity Purification followed by next-generation sequencing (TRAPseq).ResultsWe found that mice deficient in high-expressing endothelialPar1or low-expressingPar4had equivalent reductions in APAP-induced hepatic vascular instability but no effect on hepatocyte necrosis. Additionally, mice with loss of endothelialPar1andPar4had reduced permeability at an earlier time point after APAP overdose when compared to mice singly deficient in either receptor in ECs. We also found that endothelial PAR1—but not PAR4—can regulate transcription in hepatic ECs.ConclusionsLow-expressing PAR4 can react similarly to high-expressing PAR1 in APAP-overdosed hepatic ECs, demonstrating that PAR4 is a potent thrombin receptor. Additionally, these receptors are functionally redundant but act divergently in their expression and ability to influence transcription in hepatic ECs.NOMENCLATUREF2randF2rl3are the gene names for PAR1 and PAR4, respectively. For simplicity, we hereafter refer to these genes asPar1andPar4.

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“…Nor is it the intestine, the longest organ, which covers approximately 32 square meters ( Helander and Fandriks, 2014 ; Allaire et al, 2018 ). The largest organ is actually the endothelium: composed of a single layer of cells of varying shapes and sizes, the endothelium consists of approximately 10–60 trillion endothelial cells ( Aird, 2005 ; Rajala, 2021 ), covering a surface area ranging from 300 to 1000 square meters. To put this into perspective, that’s the size of a large house or one to two basketball courts.…”

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confidence: 99%