Kim A Dora1, Lyudmyla Borysova1, Xi Ye1, Chloe Powell1, Timea Z Beleznai1, Christopher P Stanley1, Vito D Bruno2, Tobias Starborg3, Errin Johnson4, Anna Pielach4, Michael Taggart5, Nicola Smart6, Raimondo Ascione2. 1. The Vascular Pharmacology Group, Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK. 2. Bristol Heart Institute and Translational Biomedical Research Centre, University of Bristol, Bristol Royal Infirmary, Upper Maudlin Street, Bristol, BS2 8HW, UK. 3. Division of Cell Matrix Biology and Regenerative Medicine School of Biological Sciences Faculty of Biology, Medical and Health Sciences, University of Manchester, B.3016 Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK. 4. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK. 5. Biosciences Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. 6. Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford, OX1 3PT, UK.
Abstract
AIMS: Coronary microvascular smooth muscle cells (SMCs) respond to luminal pressure by developing myogenic tone (MT), a process integral to the regulation of microvascular perfusion. The cellular mechanisms underlying poor myogenic reactivity in patients with heart valve disease are unknown and form the focus of this study. METHODS AND RESULTS: Intramyocardial coronary micro-arteries (IMCAs) isolated from human and pig right atrial (RA) appendage and left ventricular (LV) biopsies were studied using pressure myography combined with confocal microscopy. All RA- and LV-IMCAs from organ donors and pigs developed circa 25% MT. In contrast, 44% of human RA-IMCAs from 88 patients with heart valve disease had poor (<10%) MT yet retained cell viability and an ability to raise cytoplasmic Ca2+ in response to vasoconstrictor agents. Comparing across human heart chambers and species, we found that based on patient medical history and six tests, the strongest predictor of poor MT in IMCAs was increased expression of the synthetic marker caldesmon relative to the contractile marker SM-myosin heavy chain. In addition, high resolution imaging revealed a distinct layer of longitudinally aligned SMCs between ECs and radial SMCs, and we show poor MT was associated with disruptions in these cellular alignments. CONCLUSION: These data demonstrate the first use of atrial and ventricular biopsies from patients and pigs to reveal that impaired coronary MT reflects a switch of viable SMCs towards a synthetic phenotype, rather than a loss of SMC viability. These arteries represent a model for further studies of coronary microvascular contractile dysfunction.
AIMS: Coronary microvascular smooth muscle cells (SMCs) respond to luminal pressure by developing myogenic tone (MT), a process integral to the regulation of microvascular perfusion. The cellular mechanisms underlying poor myogenic reactivity in patients with heart valve disease are unknown and form the focus of this study. METHODS AND RESULTS: Intramyocardial coronary micro-arteries (IMCAs) isolated from human and pig right atrial (RA) appendage and left ventricular (LV) biopsies were studied using pressure myography combined with confocal microscopy. All RA- and LV-IMCAs from organ donors and pigs developed circa 25% MT. In contrast, 44% of human RA-IMCAs from 88 patients with heart valve disease had poor (<10%) MT yet retained cell viability and an ability to raise cytoplasmic Ca2+ in response to vasoconstrictor agents. Comparing across human heart chambers and species, we found that based on patient medical history and six tests, the strongest predictor of poor MT in IMCAs was increased expression of the synthetic marker caldesmon relative to the contractile marker SM-myosin heavy chain. In addition, high resolution imaging revealed a distinct layer of longitudinally aligned SMCs between ECs and radial SMCs, and we show poor MT was associated with disruptions in these cellular alignments. CONCLUSION: These data demonstrate the first use of atrial and ventricular biopsies from patients and pigs to reveal that impaired coronary MT reflects a switch of viable SMCs towards a synthetic phenotype, rather than a loss of SMC viability. These arteries represent a model for further studies of coronary microvascular contractile dysfunction.
Authors: Jaskanwal D Sara; R Jay Widmer; Yasushi Matsuzawa; Ryan J Lennon; Lilach O Lerman; Amir Lerman Journal: JACC Cardiovasc Interv Date: 2015-09 Impact factor: 11.195
Authors: Sarah J George; Song Wan; Jia Hu; Robert MacDonald; Jason L Johnson; Andrew H Baker Journal: Circulation Date: 2011-09-13 Impact factor: 29.690
Authors: Timothy R Wessel; Christopher B Arant; Susan P McGorray; Barry L Sharaf; Steven E Reis; Richard A Kerensky; Gregory O von Mering; Karen M Smith; Daniel F Pauly; Eileen M Handberg; Sunil Mankad; Marian B Olson; B Delia Johnson; C Noel Bairey Merz; George Sopko; Carl J Pepine Journal: Clin Cardiol Date: 2007-02 Impact factor: 2.882
Authors: H G Tsang; N A Rashdan; C B A Whitelaw; B M Corcoran; K M Summers; V E MacRae Journal: Cell Biochem Funct Date: 2016-02-24 Impact factor: 3.685
Authors: Kim A Dora; JinHeng Lin; Lyudmyla Borysova; Timea Beleznai; Michael Taggart; Raimondo Ascione; Christopher Garland Journal: Front Cardiovasc Med Date: 2022-08-12