Show simple item record

dc.contributor.authorLambden, Simonen
dc.contributor.authorCowburn, Andrew Sen
dc.contributor.authorMacias, Daviden
dc.contributor.authorGarrud, Tessa ACen
dc.contributor.authorKrause, Bernardo Jen
dc.contributor.authorGiussani, Dinoen
dc.contributor.authorSummers, Charlotteen
dc.contributor.authorJohnson, Randallen
dc.date.accessioned2021-05-03T23:32:01Z
dc.date.available2021-05-03T23:32:01Z
dc.date.issued2021-06-11en
dc.identifier.issn2197-425X
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/321886
dc.description.abstractBackground: The 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. Results: Under 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. Conclusions: These 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.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherSpringerOpen
dc.rightsAll rights reserved
dc.rights.uri
dc.titleEndothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2021en
prism.publicationNameIntensive care medicine experimentalen
prism.startingPage28
prism.volume9en
dc.identifier.doi10.17863/CAM.69345
dcterms.dateAccepted2021-04-27en
rioxxterms.versionofrecord10.1186/s40635-021-00390-yen
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2021-06-11en
dc.contributor.orcidMacias, David [0000-0002-8676-1964]
dc.contributor.orcidGiussani, Dino [0000-0002-1308-1204]
dc.contributor.orcidSummers, Charlotte [0000-0002-7269-2873]
dc.contributor.orcidJohnson, Randall [0000-0002-4084-6639]
dc.identifier.eissn2197-425X
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idAcademy of Medical Sciences (unknown)
cam.orpheus.counter6*
rioxxterms.freetoread.startdate2024-05-03


Files in this item

Thumbnail
Thumbnail

This item appears in the following Collection(s)

Show simple item record