Journal article
Aryl Hydrocarbon Receptor Nuclear Translocator in Vascular Smooth Muscle Cells Is Required for Optimal Peripheral Perfusion Recovery
Journal of the American Heart Association, Vol.7(11), p.n/a
06/01/2018
DOI: 10.1161/JAHA.118.009205
PMCID: PMC6015385
PMID: 29858371
Abstract
BackgroundLimb ischemia resulting from peripheral vascular disease is a common cause of morbidity. Vessel occlusion limits blood flow, creating a hypoxic environment that damages distal tissue, requiring therapeutic revascularization. Hypoxia-inducible factors (HIFs) are key transcriptional regulators of hypoxic vascular responses, including angiogenesis and arteriogenesis. Despite vascular smooth muscle cells' (VSMCs') importance in vessel integrity, little is known about their functional responses to hypoxia in peripheral vascular disease. This study investigated the role of VSMC HIF in mediating peripheral ischemic responses.
Methods and ResultsWe used Arnt(SMKO) mice with smooth muscle-specific deletion of aryl hydrocarbon receptor nuclear translocator (ARNT, HIF-1), required for HIF transcriptional activity, in a femoral artery ligation model of peripheral vascular disease. Arnt(SMKO) mice exhibit impaired perfusion recovery despite normal collateral vessel dilation and angiogenic capillary responses. Decreased blood flow manifests in extensive tissue damage and hypoxia in ligated limbs of Arnt(SMKO) mice. Furthermore, loss of aryl hydrocarbon receptor nuclear translocator changes the proliferation, migration, and transcriptional profile of cultured VSMCs. Arnt(SMKO) mice display disrupted VSMC morphologic features and wrapping around arterioles and increased vascular permeability linked to decreased local blood flow.
ConclusionsOur data demonstrate that traditional vascular remodeling responses are insufficient to provide robust peripheral tissue reperfusion in Arnt(SMKO) mice. In all, this study highlights HIF responses to hypoxia in arteriole VSMCs critical for the phenotypic and functional stability of vessels that aid in the recovery of blood flow in ischemic peripheral tissues.
Details
- Title: Subtitle
- Aryl Hydrocarbon Receptor Nuclear Translocator in Vascular Smooth Muscle Cells Is Required for Optimal Peripheral Perfusion Recovery
- Creators
- Anna Henry Borton - Case Western Reserve UniversityBryan L. Benson - Case Western Reserve UniversityLee E. Neilson - The Neurological InstituteAshley Saunders - Case Western Reserve UniversityM. Amer Alaiti - Case Western Reserve UniversityAlex Y. Huang - Case Western Reserve UniversityMukesh K. Jain - Case Western Reserve UniversityAaron Proweller - Case Western Reserve UniversityDiana L. Ramirez-Bergeron - Case Western Reserve University
- Resource Type
- Journal article
- Publication Details
- Journal of the American Heart Association, Vol.7(11), p.n/a
- DOI
- 10.1161/JAHA.118.009205
- PMID
- 29858371
- PMCID
- PMC6015385
- NLM abbreviation
- J Am Heart Assoc
- ISSN
- 2047-9980
- eISSN
- 2047-9980
- Publisher
- Wiley
- Number of pages
- 23
- Grant note
- F30 HL127985; RO1 HL128281; RO1 HL096597; T32 HL105338; T32 GM7250; TL1 RR024991; F31 NS096857; T32 NS077888; R25 HL103152 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA T32NS077888 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) R01HL096597 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) TL1TR000441 / NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Advancing Translational Sciences (NCATS) T32GM007250 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 06/01/2018
- Academic Unit
- Neurology
- Record Identifier
- 9985089125902771
Metrics
2 Record Views