CONNEXINS & DISEASES: Intercellular signalling through connexin channels - a key to the understanding of cardiovascular diseases

• Research unit: EU RFP
• Project number: 99.0368-2

Key words (English)

Connexins; gap junctions; cell communication; endothelium; vessels; hearth

Alternative project number (English)

EU project number: QLG1-1999-00516

Research programs (English)

EU-programme: 5. Frame Research Programme - 1.1.8 Generic R&D activities

Short description (English)

See abstract

Partners and International Organizations (English)

Coordinator: Centre National de la Recherche, Marseille (F)

Abstract (English)

Our task was to focus on the coupling of endothelial and smooth muscle cells of adult vessels, to assess: 1) whether the cell-to-cell communications that take place within the wall of vessels are important for the physiological functioning of these organs, particularly with regard to the control of vasomotor tone and endothelial lining, 2) the molecular and cell biological mechanism whereby changes in connexins (Cx) lead to changes in vessel function and vice-versa, 3) whether alterations in Cx-dependent communication are observed in vascular diseases. These questions were to be addressed using in vivo and in vitro models of rodent cells, that closely mimic the situations these cells face in humans under (patho)physiological conditions. These generals aims were to be addressed by studying the following four specific topics :
1. task 1 : the in vivo expression of connexins and coupling in endothelial and smooth muscle cells of different regions of the vascular tree, under normal and pathological conditions (e.g. experimental hypertension).
2. task 2 : the in vitro influence of connexins on the migration and growth of endothelial and smooth muscle cells, using monolayers of wild type and transfected cells subjected to mechanical wounding.
3. task 3 : the in vitro modulation of connexin expression by changes in fluid pressure, flow rate and/or shear stress, using cell monolayers and flow tube cultures mimicking the cell organization of native vessels.
4. task 4 : the specific functions of vascular connexins, as evaluated after blockade or over-expression of individual connexins in vascular cells transfected with dominant negative connexins or isolated from transgenic mice over- or under-expressing one of these proteins.
Specifically, we have found that :
1. Connexins 40 and 43 are differentially regulated within the kidneys of hypertensive rats
2. t-plasminogen activator colocalizes with von Willebrand factor in human endothelial cells
3. Endothelial wound repair is inhibited by dominant negative connexin inhibitors
4. Mutations of human Cx26 and Cx30 affect the function of human keratinocytes.
5. SNPs of human Cx36 confer a susceptibility for juvenile myoclonic epilepsy
6. Cx36 controls insulin secretion of MIN6 cells
7. Cx43 has an essentially endothelial distribution in vessels of transgenic mice
8. Cx 43 and Cx26 are differentially regulated during bladder outlet obstruction
9. P2 phosphorylation of Cx43 is not obligatory for coupling of tumoral insulin-producing cells
10. Cx43 modulates the differentiation of neural progenitor cells in vitro

References in databases (English)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 99.0368-2