Vascular Function In Atherosclerosis

Atherosclerosis is a condition where arteries become narrowed by a gradual build up of fatty material in their walls (plaque), and functional changes occur within vascular endothelium and smooth muscle during disease progression. Blood vessel diameter determines blood pressure and the contraction and relaxation of smooth muscle in the artery wall is controlled by intracellular calcium concentration. We have shown that the activity of pumps and proteins which regulate smooth muscle calcium concentration are altered in atherosclerosis, and we are investigating how a protein kinase called AMPK is involved.

Atherosclerosis:

Research in my laboratory is focused on blood vessel structure and function during the pathogenesis of atherosclerosis, a progressive condition of the vasculature which can lead to life-threatening occlusive events. Atherosclerotic plaques give rise to cardiovascular disease (CVD), a leading cause of morbidity and mortality worldwide. Plaques commence when a sustained insult to the vascular endothelium, such as hypertension or exposure to free radicals, initiates endothelial dysfunction and the establishment of an inflammatory focus. Lesions tend to form at areas with turbulent blood flow, including bifurcations and branches, suggesting that the cyclic strain at these sites may also contribute to the atherosclerotic process. Atherosclerosis progresses slowly, causing narrowing of the artery lumen and reduced blood flow. Plaque rupture and resulting thrombosis manifest as acute myocardial infarction or stroke.

Vasorelaxation and smooth muscle calcium handling:

Abnormal vascular constriction and relaxation in atherosclerotic blood vessels can be attributed to a combination of reduced nitric oxide (NO) bioavailability and altered smooth muscle cell function. The fundamental second messenger for smooth muscle contraction and relaxation is Ca²⁺; with increased levels of cytosolic Ca²⁺ initiating activation of myosin light chain kinase (MLCK) and subsequent contraction. Relaxation is achieved when cytosolic Ca²⁺ concentrations return to resting levels. The sarcoplasmic reticulum (SR) provides important regulatory control; Ca²⁺ release mainly being governed by IP3 receptors (IP3R) and ryanodine receptors (RYR) and re-uptake being achieved via the Sarco/Endoplasmic Reticulum Ca²⁺ ATPase (SERCA). Ca²⁺ may also be extruded into the extracellular space via the Plasma Membrane Ca²⁺ ATPase (PMCA) or the sodium/Ca²⁺ exchanger (NCX).

We have demonstrated that vascular responses are altered as atherosclerosis develops, and this is linked to altered expression and/or function of Ca²⁺ regulatory proteins within smooth muscle.

AMP-activated protein kinase:

AMP-activated protein kinase (AMPK) is expressed in endothelium and vascular smooth muscle and has potential vasculoprotective effects. Investigations in my laboratory are ongoing in order to define the role of AMPK in blood pressure control, vascular relaxation and the function of calcium handling proteins in heath and cardiovascular disease. Our hypothesis is that AMPK is an important determinant of vascular smooth muscle function and the consequences of disrupted AMPK activity in disease may be mediated through altered expression or function of Ca²⁺ regulatory proteins. Pharmacological, physiological, biochemical and molecular techniques are utilised to investigate AMPK and its downstream targets in normal and atherosclerotic vasculature and these studies will provide insight into the mechanisms of vascular dysfunction in diseased arteries and reveal viable therapeutic targets.

Selected Publications:

1. Ewart M-A, and Kennedy S. Diabetic cardiovascular disease AMP-activated protein kinase (AMPK) as a therapeutic target. Cardiovascular and Hematological Agents in Medicinal Chemistry 2012;10:190-211.
2. Watt J, Ewart M-A, Greig FH, Oldroyd K, Wadsworth RM, and Kennedy S.  The effect of reactive oxygen species on whole blood aggregation and the endothelial cell-platelet interaction in patients with coronary heart disease. Thrombosis Research 2012;130:210-215.
3. Ewart M-A, Kennedy S. AMPK and vasculoprotection. Pharmacology and Therapeutics 2011;131:242-253.
4. Ewart M-A, McCarron JG, Kennedy S, Currie S. SERCA and IP3R expression and function in vascular smooth muscle are altered throughout atherosclerotic progression. Biophysical Journal 2010;98:677a.
5. Ewart M-A, Kohlhaas CF, Salt IP. Inhibition of Tumor Necrosis Factor {alpha}-Stimulated Monocyte Adhesion to Human Aortic Endothelial Cells by AMP-Activated Protein Kinase. Arteriosclerosis Thrombosis and Vascular Biology 2008;28:2255-2257.