Cerebral Circulation

Earlier in my career, I made contributions in the areas of myocardial ischemic dysfunction, pericardium constraint, and venous capacitance.  For the past 15 years, my attention has turned increasingly to wave propagation in the arterial and venous vasculature.  I have used “wave intensity analysis”, a method of analyzing blood pressure and velocity developed by Professor Kim Parker that defines the power/energy associated with forward- or backward-traveling waves and whether they increase pressure (compression waves) or decrease pressure (decompression waves) as they pass.  More recently, I and my trainees developed the “reservoir-wave approach”, the central thesis of which is that measured pressure should be understood as the instantaneous sum of a volume-related pressure (i.e., reservoir or Windkessel pressure) and a wave-related pressure (i.e., excess pressure).  Reservoir pressure is calculated by assuming that the change in reservoir pressure is proportional to its change in volume.  We subtract reservoir pressure from measured pressure and perform wave intensity analysis on excess pressure.  This approach enabled us to define wave propagation and reflection in the canine aorta and to show how it is modified by vasodilatation and vasoconstriction.  This approach also enabled us to divide systemic vascular resistance into its series components: large-artery, arterial reservoir, micro-circulatory, venous reservoir, and large-vein resistances.

Using this approach, I and Dr. Marc Poulin last year applied for and received a CIHR grant to study the cerebral circulation.  Not surprisingly, our preliminary data led us to hypothesize that hypercapnia and hypoxia will decrease total cerebral vascular resistance and hypocapnia will increase it. The decreases in resistance with hypercapnia and hypoxia will be partially accounted for by decreases in micro-circulatory resistance and the increase with hypocapnia, by an increase in arterial reservoir resistance.  The preliminary data also led us to hypothesize that P∞, a model-based parameter that is the pressure at which arterial outflow would stop theoretically, will decrease with both hypocapnia and hypoxia.  These insights may prove to be important, clinically.

I completed my MD at the University of Alberta and subsequently my residency training in neurosurgery at the University of Calgary. Following this, I completed two years of clinical fellowships at the Barrow Neurological Institute in Phoenix, Arizona; one year in cerebrovascular/skull base neurosurgery with Dr. Robert F. Spetzler, and an additional year in endovascular neurosurgery with Dr. Felipe C. Albuquerque and Dr. Cameron G. McDougall. During residency, I completed a master’s degree in biomedical engineering at Harvard University, allowing me to cultivate my research interests.

My primary research interests involve the use of tissue engineering techniques to treat cerebrovascular disorders. Specifically, my graduate degree focused on endothelial progenitor cells embedded in a biopoymer to treat intracranial aneurysms. Tissue engineering techniques, however, can also be used to treat other conditions such as atherosclerotic disease and stroke. A secondary interest of mine is the development of novel biomedical materials and devices to act as scaffolds for the local delivery of engineered cells and tissue factors.   

Regulation of cellular functions by second messengers, with emphasis on protein phosphorylation and the control of smooth muscle contraction. The molecular basis of myogenic tone in the cerebral vasculature (in collaboration with Dr. Bill Cole). The mechanism of regulation of urethral smooth muscle contraction by Rho-associated kinase. Calcium sensitization of smooth muscle contraction. Calcium-independent phosphorylation of myosin. The mechanism of activation of myosin light chain kinase by calcium and calmodulin. The roles of protein kinase C and Rho-associated kinase in phosphorylation and inhibition of myosin light chain phosphatase and the phosphatase inhibitor CPI-1. Regulation of delayed rectifier potassium current in vascular smooth muscle (in collaboration with Dr. Bill Cole). Development of highly sensitive proteomic methods for the analysis of myosin phosphorylation in the renal microvasculature (in collaboration with Dr. Rodger Loutzenhiser).

Research projects in my laboratory focus on 1) the roles, regulation, properties and molecular basis of voltage-gated and ATP-sensitive potassum and non-selective cation channels in vascular smooth muscle cells, and 2) mechanisms of myofilament Ca2+ sensitization, in the context of the myogenic response of resistance arteries to elevations in intravascular pressure. These studies are primarily directed towards understanding the regulation of cerebral arterial diameter and, thereby, blood flow to the brain, in health and disease.

We employ several techniques to accomplish our research goals, including: 1) conventional microelectrodes and patch clamp methodologies to monitor membrane potential and ion currents (whole cell and single channel) in intact smooth muscle tissues and isolated myocytes, respectively; 2) Ca2+ fluorescence monitoring techniques, video microscopy and pressurized arterial myography to relate changes in membrane potential and ionic currents to specific alterations in intracellular Ca2+ levels, contractile tone and vessel diameter; 3) molecular biological and biochemical studies on vascular smooth muscle channels to identify the molecular composition of the channels, their association with non-channel proteins, and specific structure-function relationships in the channel proteins; 4) immunocyto-chemical approaches for identification of ion channel subunit expression and intracellular trafficking in vascular smooth muscle. 5) biochemical approaches for detection of protein/phosphoprotein levels in pressurized arterial segments.

Summary: Brain blood flow is exquisitely controlled by local changes in brain activity in order to deliver appropriate amounts of oxygen and glucose to desired regions. A spectrum of neurological problems are closely linked to abnormalities in brain blood flow, yet surprisingly we know very little about how brain cells signal to blood vessels to regulate this process. My laboratory will use new fluorescence microscope technologies to image within the brain at the cellular level to study how brain cells communicate with blood vessels. By understanding the molecular mechanisms of this process, my research will discover new targets for disease intervention.

The cellular mechanisms recruited during cerebral blood flow (CBF) control are complex and the specific contribution of neurons and astrocytes are highly controversial as they have been difficult to tease apart using traditional methods. This is due, in part, to an inability to activate or inhibit specific cell populations to causally determine how different cell-types contribute to this process. Using recent technical innovations, my immediate goals are to use an acute brain slice preparation to 1) determine how neurons and astrocytes participate in CBF control separately and how they interact with each other, and 2) identify novel cellular pathways in neurons and astrocytes that play an important role in changing the diameter of cerebral blood vessels. My long-term goals are to 1) extend or refine the in vitro findings in vivo and 2) discovery new aspects of brain signaling and CBF control by imaging fully awake behaving animals.

1. Effects of exercise on cerebral blood flow and age-related cognitive decline in older adults;
2. Regulation of cerebral blood flow in obstructive sleep apnea;
3. Mechanisms of cerebral blood flow regulation

The interests of our research group bridge integrative human physiology with molecular mechanisms of cerebral blood flow regulation. We have developed a translational research program using basic physiology to address important health-related issues. Important collaborations have been established to address basic physiological problems in clinical settings. These include studies of cerebral blood flow regulation and relations to autonomic function, cardiorespiratory control, renal blood flow, sleep, and cognitive function in health and disease.

In summary, we have a novel research program on Cerebral Blood Flow Regulation that includes solid approaches in integrative physiology to better understand basic mechanisms of regulation and important clinical problems of the cerebral circulation. Our work spans from the bench to the bedside, the whole human to single molecules, and healthy aging. We envision that our studies will help us better understand the role of exercise in reducing cognitive decline in older men and women, and that we will better understand the pathophysiology of OSA and stroke, and integral step to develop new therapeutic approaches. Finally, our work will lead to the creation of new knowledge which has the potential for novel and significant clinical translation and imporved health for Canadians.

Stroke outcomes can be modified by medical therapy, yet abundant research shows that proven treatments are under-utilized or inappropriately utilized in community practice. My outcomes research program seeks to identify predictors of appropriate medical care for stroke and the impact of stroke treatments in the “real world” setting outside the context of highly monitored clinical trials. I direct scientific research in the U.S. national Get With The Guidelines Stroke Registry of more than one million stroke hospital admissions.