Department of Drug Design and Pharmacology > Employees
Molecular and Cellular Pharmacology
Universitetsparken 2, 22, Building: C431
2100 København Ø
At the present time, studies are being conducted to investigate the mechanism behind changes in vascular reactivity in left intramural and septal coronary arteries following acute myocardial ischemia with or without subsequent reperfusion. Furthermore, the effect of organ culture in the presence of lipopolysaccharide (LPS) and angiotensin II on the vasomotor responses of coronary arteries are currently being investigated. These studies increase our knowledge of complex mechanism (cytokine pathway, Toll-like receptor, MAPK pathway etc.) behind regulation of arterial tone and contractility in the cardiovascular system under different pathological conditions, which will improve diagnosis and treatment of patients suffering from ischemic cardiovascular diseases.
Primary fields of research
Through my scientific career, I have been focusing on the regulation of vascular tone in health and disease (diabetes type I and II, stroke, hypertension, congestive Heart Failure and age-related changes).
Coronary arteries are densely innervated by sensory nerve endings containing calcitonin gene-related peptide (CGRP). CGRP is a potent naturally occuring 37 amino acid vasodilatory neuropeptide which is released from the perivascular sensory nerve endings in the wall of flow regulating intramural coronary arteries during hypoxia and by low pH levels in the myocardium, thus suggesting a vasodilatory role under ischemic conditions.
Receptor subtypes for CGRP, the intracellular signalling pathways and the mechanism behind CGRP-induced desensitization are still under investigation in both resistance and conductance arteries of different species including human. So far, these studies clearly demonstrate a larger CGRP receptor density in resistance arteries (internal lumen diameter < 200 µm) compared to larger conductance arteries (internal lumen diameter > 200 µm), indicating that receptor distribution, calcium handling, ion channels and second messengers may be finely adjusted within the circulatory system, probably reflecting the physiological demands on the vascular segments.
CGRP receptor consists of three components, calcitonin receptor-like receptor (CLR), a specific chaperone called receptor activity modifying protein 1 (RAMP1) and receptor component protein (RCP). A novel family of chaperone proteins, called RAMPs (RAMP1, RAMP2 and RAMP3) were identified as proteins escorting CLR to the plasma membrane to generate either CGRP (when associated with RAMP1) or adrenomedullin receptors (when associated with RAMP2 or RAMP3). CLR belongs to class B of the G protein-coupled receptor (GPCR) family and is linked to Gs protein. It was recently reported that the small non-peptide CGRP receptor antagonists (olcegepant and telcagepant) act by blocking access of CGRP to the peptide-binding cleft at the interface of CLR and RAMP1.
Our recent studies on human subcutaneous arteries clearly show that key components of the CGRP receptor (CLR and RAMP1) are located on both smooth muscle and endothelial cells. Despite the presence of functional endothelium in these human vessels (verified by functional studies using carbachol, substance P and bradykinin), the contribution of the endothelium to CGRP-induced vasodilation seems to be insignificant. Perhaps, the CGRP receptors located on the endothelium have different biological effects than being directly involved in the vasomotor control or the density of CGRP receptors are significantly higher on smooth muscle cells compared with the endothelium. Recent studies have shown that CGRP acts as a pro-angiogenic growth factor by increasing the secretion of vascular endothelial growth factor and expression of focal adhesion kinase, thereby contributing to remodelling. In addition, our recent results show that 10 nM telcagepant significantly antagonizes the reduction in tension by CGRP but not the reduction in calcium. It is possible that the conformation of the CGRP receptor that eventually leads to a reduction in intracellular calcium is not the same as that needed for inhibition of relaxation and is therefore less sensitive to the antagonist.
These results will shed light on the complex signalling pathway behind CGRP-induced vasodilatation and desensitization including its role under different circulatory complications such as stroke, ischemia, hypertension and migraine.
Over 15 years of teaching experience in the field of Pharmacology covering wide range of areas: Cardiovascular Pharmacology, Endocrinology (diabetes and obesity), Receptor Pharmacology and Intracellular Signaling Pathways, and Pharmacokinetics and –dynamics.
Supervision of students:
Supervised over 60 Master Thesis students and 15 PhD-students.
Course in supervision of PhD-students:
8th and 9th of September 2009 and 27th of October 2009: PUMA course in supervision of PhD-students at the University of Copenhagen.
Member of didactic committee at the Faculty of Pharmaceutical Sciences and Chairman of the teaching committee at the Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen: from January 2008 - March 2012
August 2012 - present : Member of the committee for Research and Innovation (FIU) at the Dept. of Drug Design and Pharmacology, University of Copenhagen.
Pedagogic course for PhD-students (November 1996, 30 lectures distributed over 3 days): Teaching and learning, Royal Danish School of Pharmacy, Instructor: Associate Professor, Arne Jakobsen.
23 august 2001 - 1 september 2002: Pedagogic training for Assistant Professors at Danish Universities, The Danish University of Pharmaceutical Sciences. Holder of certificate for Higher Education Teaching and Teaching Practice (signed by the Rector, Prof. Sven Frøkjær 11. April 2003).
Fields of interest
Cardiovascular and muscle Pharmacology: Diabetes, obesity, Migraine and cardiac pain and nociception
Receptor pharmacology and intracellular signaling pathways
Fluorescence microscopy and measurements of intracellular calcium concentration
Pharmacokinetics and pharmakodynamics (PK-PD studies)