The initiation, modulation and resolution of thrombus associated with eroded or
unstable coronary plaques are critical determinants of acute coronary events. This
itself is dependent on the cellular function of the surrounding endothelium and
vascular wall. In particular, the regulation of vascular tone and the acute release of
tissue plasminogen activator by the endothelium make important contributions to the
defence against intravascular thrombosis. These aspects of endothelial function will
provide major new insights into the pathophysiology of cardiovascular disease, and
to shape future therapeutic interventions.
The experimental medicine models presented here originate from an early interest in
exploring these novel aspects of endothelial function, and in particular, the acute
release of the endothelium-derived fibrinolytic factor, tissue plasminogen activator.
This model was initiated, developed and applied to a diverse range of physiological
and pathophysiological circumstances that have informed health and disease.
Publications are grouped into 5 main sections.
Section 1 describes the early validation and exploration of the model to stimulate
acute tissue plasminogen activator release using a variety of physiological and
pathophysiological mediators. This describes the early identification of potent
stimulators of acute tissue plasminogen activator release including substance P,
bradykinin, desmopressin and thrombin receptor agonists. This work was extended to
demonstrate the important role of nitric oxide and vascular inflammation in this
process. Subsequent sections cover the application of these techniques in patient
populations with a predisposition to cardiovascular disease (Section 2) as well as
with established (Section 3) and end-stage disease (Section 4). These sections also
explore the potentially important modulation of the renin-angiotensin system with
particular reference to angiotensin-converting enzyme inhibition and the role of
bradykinin. Section 5 contains some miscellaneous work and reviews of the subject
area bring together the key aspects of the field as well as an important study to
address the vascular endothelial function in patients with a rare haematological
deficiency, type 3 von Willebrand disease.