John McGuire

Canadian Institutes of Health Research New Investigator.

This research is funded by grants from the Canadian Institutes of Health Research, the Government of Newfoundland and Labrador, Canada Foundation for Innovation and Memorial University.

Cardiovascular Pharmacology and Physiology

Research Methods:

• Isometric tension and microelectrode recordings in isolated blood vessels from transgenic and inbred animals.
• Long-term blood pressure, heart rate and locomotor activity recordings by radiotelemetry in conscious mice.
• With collaborators at Memorial University (Drs. Smeda, Van Vliet, Brosnan, Bertolo, Kaur, Tabrizchi) we have been looking at endothelial function and dysfunction in different models of cardiovascular disease including genetic and salt-induced hypertension, stroke, type 2 diabetes and maternal diet programming of offspring.

Endothelial - Vascular Smooth Muscle Cell Interactions: Many cardiovascular diseases are accompanied by changes to the interactions between endothelial and vascular smooth muscle cells in blood vessels. Our previous studies utilized transgenic mouse models to investigate these interactions under control conditions of normal vascular health. These studies revealed multiple signaling pathways modulate vascular smooth muscle tone (i.e. vasodilation) through receptors found on endothelial cells. Recently we have been investigating mechanisms that link endothelial cells to vascular smooth muscle cell function during conditions of so-called endothelial dysfunction.

Endothelium-dependent hyperpolarization of vascular smooth muscle cells: One signaling pathway that mediates vasodilation has become a focus of our laboratory's research. The mechanism involves the activation of the endothelial G protein coupled receptor PAR2 (see below) that results in hyperpolarization of the underlying vascular smooth muscle cells. This endothelium-dependent hyperpolarization leads to the inactivation of voltage-dependent calcium channels and reduced extracellular calcium entry into the cell and thus, relaxation of vascular smooth muscle. Our laboratory is investigating putative mediators and precise mechanisms that are responsible for this effect of the endothelium on vascular smooth muscle.

Proteinase-Activated Receptor 2: This receptor (abbreviated PAR2) was the second of 4 plasma membrane receptors that have been found to be activated by certain serine proteinases via the unmasking of self-contained "tethered ligand" peptide sequences within the N-terminal segments of these 7 transmembrane domain G protein-coupled receptors. Both physiological and pathophysiological processes have been proposed as consequences of PAR2 activation. We are investigating the pathophysiological role of PAR2 in cardiovascular health and diseases.

PAR2 and cardiovascular diseases: We have proposed that PAR2 may have role in modulating hemodynamic regulation of the cardiovascular system under normal and disease states because it appears to be unaffected by endothelial dysfunction during hypertension. We believe it is important to understand the role of PAR2 in cardiovascular regulation because there has been a significant effort in the design of drugs to treat inflammatory diseases based on PAR2 i.e. agonists and antagonists. The impact that such drugs will have on the cardiovascular system will need to be investigated.

Selected Research Articles

1. Persistence of PAR₂ relaxation in BPH/2 hypertensive mice. McGuire JJ, Van Vliet BN, King JC, Gimenez J, Halfyard SJ. Pflügers Archiv European Journal of Physiology – in press 2/2007 doi:10.1007/s00424-007-0226-2

2. Effects of post-stroke losartan versus captopril treatment on cerebrovascular myogenic and endothelial function of SHRsp. Smeda JS and McGuire JJ. Stroke – in press 3/2007 doi:10.1161/strokeaha.106.475087

3. Hyperpolarization of vascular smooth muscle by the activation of endothelial Proteinase-Activated Receptor 2 in murine small mesenteric arteries. McGuire JJ, Hollenberg MD, Bennett BM, Triggle CR. Can J Physiol Pharmacol 82(12):1103-1112, 2004.

4. 2-furoyl-LIGRLO-amide: a highly potent and selective PAR-2 agonist. McGuire JJ, Saifeddine M, Triggle CR, Sun K, Hollenberg MD. J Pharmacol Exp Ther 309(3):1124-31, 2004.

Selected Reviews

1. Phenotyping the level of mouse blood pressure by telemetry. Van Vliet BN, McGuire JJ, Chafe L, Leonard A, Joshi A, Montani JP. Clin Exp Pharmacol Physiol. 33(11):1007-15 2006

2. PAR₂: A challenging new target for treatment of vascular diseases. McGuire JJ. Current Pharmaceutical Design. 10(22):2769-2778. 2004.

3. Endothelium-derived relaxing factors – A focus on Endothelium-Derived Hyperpolarizing Factor(s). McGuire JJ, Ding H, Triggle CR. Can J Physiol Pharmcol 79(6): 443-470, 2001.