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Regulation of smooth muscle receptor expression in vascular disease

Principal investigator; Edvinsson, Lars, Professor, MD/PhD

Clinical speciality: Medicine

Phone: ++4646171484

Co-workers: Saema Ansar, Cang-Bao Xu

Cardiovascular disorders are associated with marked alterations in the vessel walls; we have found that the smooth muscle cell receptors were upregulated and have characterized these with functional and molecular methods. Organ culture was found to induce similar type of upregulation of endothelin (ETA, ETB), angiotensin II (AT1, AT2) and 5-hydroxytryptamine (5-HT1B) receptors in the blood vessels, and in patients as that seen following acute stroke. This process is mediated via de novo transcription and translation of the associated G-protein coupled receptors. This is supported by studies of experimental focal cerebral ischemia and subarachnoid hemorrhage demonstrating a similar type of receptor upregulations. The aim of our ongoing work is to examine how this process is triggered; which signal-transduction mechanisms and transcription factors are involved.

To achieve the objectives we have set up a range of very specific methods:
Realtime-PCR for quantitative determination of mRNA.
Protein expression is studied with quantitative Western blot and the proteins are localized with confocal immunohistochemistry.
To examine functional responses in isolated tissue we use the FURA-2 method for analysis of intracellular calcium in both cells and vessel segments.
The localization of the signal substances and receptors are studied with immunohistochemistry and confocal microscopy. Functional studies of receptors are performed by in vitro methods such as the Mulvany tissue chambers and with perfused isolated vessels where the agonists/antagonists are applied luminal or abluminal to circumvent the blood-brain barrier.
Induction of experimental cerebral ischemia with permanent occlusion or reperfusion, and subarachnoid hemorrhage (SAH) in rats are used to examine vascular receptor changes at several levels.

It is our hypothesis that there are changes in receptor expression in vascular disease. By pinpointing the signal-transduction mechanisms involved, we may find new therapeutic targets for cerebrovascular diseases. The initial therapeutic studies are promising.

Link to project homepage: http://www.med.lu.se/klinvetlund/medicin

5 recent original publications

Waldsee R, Ahnstedt H, Eftekhari S, Edvinsson L
Involvement of calcium-calmodulin dependent protein kinase II in endothelin receptor expression in rat cerebral arteries
American Journal of Physiology Heart Circ Physiol. 2010; online: 0

Maddahi A, Chen Q, Edvinsson L
Enhanced cerebrovascular expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 via the MEK/ERK pathway during cerebral ischemia in the rat
BMC Neuroscience . 2009; 10: 56

Chen Q, Edvinsson L, Xu CB
Role of ERK/MAPK in endothelin receptor signaling in human aortic smooth muscle cells.
BMC Cell Biol. 2009; 10: 52

Ansar S, Edvinsson L
Cerebrovascular ETB, 5-HT1B, and AT1 receptor upregulation correlates with reduction in regional CBF after subarachnoid hemorrhage.
Am J Physiol Heart Circ Physiol . 2007; 293: H3750-8

Ansar S, Edvinsson L
Subtype activation and interaction of protein kinase C and mitogen-activated protein kinase controlling receptor expression in cerebral arteries and microvessels after subarachnoid hemorrhage
Stroke. 2008; 39: 185-90

Further publications here (new window)

Financing/year