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Abstract
Background: Adequate blood flow into coronary micro-arteries is essential for myocardial function. Here we assess the
mechanisms responsible for amplifying blood flow into myogenically-contracting human and porcine intramyocardial micro-arteries
ex vivo using endothelium-dependent and -independent vasodilators.
Methods: Human and porcine atrial and ventricular small intramyocardial coronary arteries (IMCAs) were studied with pressure
myography and imaged using confocal microscopy and serial section/3-D reconstruction EM.
Results: 3D rendered ultrastructure images of human right atrial (RA-IMCAs) revealed extensive homo and hetero-cellular contacts,
including to longitudinally-arranged smooth muscle cells (l-SMCs) found between the endothelium (ECs) and radially-arranged medial
SMCs (r-SMCs). Local and conducted vasodilatation followed focal application of bradykinin in both human and porcine RA-IMCAs, and
relied on hyperpolarization of SMCs, but not nitric oxide. Bradykinin initiated asynchronous oscillations in endothelial cell Ca2+ in
pressurized RA-IMCAs and, as previously shown in human RA-IMCAs, hyperpolarized porcine arteries. Immunolabelling showed smalland intermediate-conductance Ca2+-activated K+ channels (KCa) present in the endothelium of both species and concentrationdependent vasodilation to bradykinin followed activation of these KCa channels. Extensive electrical coupling was demonstrated
between r-SMCs and l-SMCs, providing an additional pathway to facilitate the well-established myoendothelial coupling. Conducted
dilation was still evident in a human RA-IMCAs with poor myogenic tone, and heterocellular contacts were visible in the 3D
reconstructed artery. Hyperpolarization and conducted vasodilation was also observed to adenosine which, in contrast to
bradykinin, was sensitive to combined block of ATP-sensitive (KATP) and inwardly rectifying (KIR) K+ channels.
Conclusions: These data extend our understanding of the mechanisms that coordinate human coronary microvascular blood flow
and the mechanistic overlap with porcine IMCAs. The unusual presence of l-SMCs provides an additional pathway for rapid
intercellular signalling between cells of the coronary artery wall. Local and conducted vasodilation follow hyperpolarization of the
ECs or SMCs, and contact-coupling between l-SMCs and r-SMCs likely facilitates this vasodilation.
mechanisms responsible for amplifying blood flow into myogenically-contracting human and porcine intramyocardial micro-arteries
ex vivo using endothelium-dependent and -independent vasodilators.
Methods: Human and porcine atrial and ventricular small intramyocardial coronary arteries (IMCAs) were studied with pressure
myography and imaged using confocal microscopy and serial section/3-D reconstruction EM.
Results: 3D rendered ultrastructure images of human right atrial (RA-IMCAs) revealed extensive homo and hetero-cellular contacts,
including to longitudinally-arranged smooth muscle cells (l-SMCs) found between the endothelium (ECs) and radially-arranged medial
SMCs (r-SMCs). Local and conducted vasodilatation followed focal application of bradykinin in both human and porcine RA-IMCAs, and
relied on hyperpolarization of SMCs, but not nitric oxide. Bradykinin initiated asynchronous oscillations in endothelial cell Ca2+ in
pressurized RA-IMCAs and, as previously shown in human RA-IMCAs, hyperpolarized porcine arteries. Immunolabelling showed smalland intermediate-conductance Ca2+-activated K+ channels (KCa) present in the endothelium of both species and concentrationdependent vasodilation to bradykinin followed activation of these KCa channels. Extensive electrical coupling was demonstrated
between r-SMCs and l-SMCs, providing an additional pathway to facilitate the well-established myoendothelial coupling. Conducted
dilation was still evident in a human RA-IMCAs with poor myogenic tone, and heterocellular contacts were visible in the 3D
reconstructed artery. Hyperpolarization and conducted vasodilation was also observed to adenosine which, in contrast to
bradykinin, was sensitive to combined block of ATP-sensitive (KATP) and inwardly rectifying (KIR) K+ channels.
Conclusions: These data extend our understanding of the mechanisms that coordinate human coronary microvascular blood flow
and the mechanistic overlap with porcine IMCAs. The unusual presence of l-SMCs provides an additional pathway for rapid
intercellular signalling between cells of the coronary artery wall. Local and conducted vasodilation follow hyperpolarization of the
ECs or SMCs, and contact-coupling between l-SMCs and r-SMCs likely facilitates this vasodilation.
| Original language | English |
|---|---|
| Article number | 980628 |
| Pages (from-to) | 1-39 |
| Number of pages | 39 |
| Journal | Frontiers in Cardiovascular Medicine |
| Volume | 9 |
| Early online date | 26 Jul 2022 |
| DOIs | |
| Publication status | Published - 12 Aug 2022 |
Bibliographical note
Funding Information:This work was supported by the British Heart Foundation (BHF) and Medical Research Council (MRC) Grants to RA [Grant Numbers BHF: PG/18/49/33833, IG/14/2/30991, PG/16/104/32652, and MRC MR/L012723/1] and by the Bristol NIHR Biomedical Research Center. Organ Donor Heart Collection was funded by the NIHR Cambridge/Newcastle Blood and Transplant Research Unit (BTRU). In addition, this work was supported by British Heart Foundation Grants to KD [Grant Numbers FS/08/033/25111, FS/13/16/30199, IG/13/5/30431, PG/18/11/33552, and PG/20/10260] and by the Oxford BHF Centre of Research Excellence [Grant Number RE/13/1/30181].
Funding Information:
We thank the research nurses, lab technicians and surgeons at the Bristol Heart Institute, University Hospital NHS Foundation Trust, Bristol Trials Centre (Clinical Trials and Evaluation Unit) at the University of Bristol, and the staff at the University of Bristol Translational Biomedical Research Centre, a national research facility for large animals co-funded by the BHF and MRC. We appreciate the assistance of Prof. John Dark, Dr. Lu Wang, and Lucy Bates (Newcastle) in organ retrieval and biopsy provision. We express our full gratitude to all the patients taking part in this study. Finally we thank Dr. Lauren Phillips for her guidance regarding 3D rendering of the arteries.
Publisher Copyright:
Copyright © 2022 Dora, Lin, Borysova, Beleznai, Taggart, Ascione and Garland.
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Dive into the research topics of 'Signaling and structures underpinning conducted vasodilation in human and porcine intramyocardial coronary arteries'. Together they form a unique fingerprint.Projects
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Arterial bioengineering of decellularised human saphenous veins to reduce early graft thrombosis and improve long-term patency rate
Bond, A. R. (Principal Investigator)
1/06/17 → 31/05/20
Project: Research