Endothelial caveolae are functional microcompartments and target structures in hypertension and renal failure

Prof. Dr. Joachim Hoyer

Department of Internal Medicine and Nephrology
Philipps-Universitaet Marburg
Baldingerstrasse 1
35033 Marburg

Phone: +49 6421 58 66 480
Fax: +49 6421 58 66 365
hoyer@med.uni-marburg.de
Homepage: www.uni-marburg.de/fb20

Project description:

This project aims to clarify mechanisms of endothelial dysfunction in disease states. In many cardiovascular diseases a dysfunction of the vascular endothelium occurs in the very early phase of disease development. The knowledge of pathophysiologically relevant alterations of endothelial function and development of therapeutic strategies directed to recover endothelium function will enable an early stage intervention in cardiovascular diseases.

Endothelium plays a pivotal role in the regulation of vascular function as it is situated at the interface between blood flow and the surrounding tissue and is therefore directly subjected to humoral and hemodynamic stimuli associated with blood flow .

In response to such stimuli like vasoactive factors or shear stress the endothelium synthesises and secrets vasoactive compounds which regulate the tone of vascular smooth muscle cells and thereby alter vascular tone and blood flow. An important characteristic of endothelial function is the ability to sense changes in hemodynamic forces like shear stress and the subsequent induction vascular smooth muscle relaxation and subsequent vasodilation. This endothelial feature protects the blood vessel wall from damage by shear stress and enables an increase in blood flow for the supply of downstream tissues. The endothelial mechanism of sensing hemodynamic forces is incompletely understood and in the direct focus of the project as it might become a new target of therapeutic intervention.

The hypothesis of the project is that endothelial caveolae form membrane microcompartments for hemodynamic sensing and harbour specific ion channels and enzymes which form a mechanosensitive functional complex to convert physical hemodynamic forces into biochemical signals (Fig.2).

In the first funding period we found that Ca²⁺-permeable TRPV4 and K⁺-permeable K_Ca2.3 channels co-localise together with NO synthase in caveolae and are regulated by Cav-1 protein. We demonstrated that they functionally interact and form a multiprotein complex that is essential for mechanosensitive vasodilation. We aim to characterise extra- and intracellular mechanisms that regulate the integration of ion channels into the caveolar mechanotransduction complex and their functional interaction.

We established several experimental disease models for hypertension and renal failure which will enable us to test whether alterations of the caveolar mechanotransduction complex are involved or causative in endothelial dysfunction in cardiovascular disease like hypertension and renal failure.

Major goals:

A. Characterisation of the caveolar microcompartment with respect to mechano­sensitivity:

1) clarify whether mechanosensitivity-associated ion channels TRPV4 and K_Ca2.3 are co-localised in caveolae and are part of a mechanotransduction complex

2) characterise the role of the caveolar compart­ment in the mechanotransduction by mechanical or hemodynamic stimuli

B. Characterising the alteration of caveolar mechanotransduction and caveolar compartmentation in experimental models of hypertension and renal failure.

Staff:

Tascher, PhD Biology
Goedicke, PhD Biology
Eggert, PhD Biology
Andreas Hofmeister, Graduate Student Biology
Michael Kacik, M.D.
Christoph Busch, M.D., Postdoc
Ivica Grigic, M.D., Research associate
J. Hoyer, M.D.

Selection of recent publications:

1. Grgic I, Kiss E, Kaistha BP, Busch C, Kloss M, Sautter J, Müller A., Kaistha A, Schmidt C, Raman G, Wulff H, Strutz F, Gröne H-J, Köhler R, Hoyer J.

Renal fibrosis is attenuated by targeted disruption of KCa3.1 potassium channels.   

Proc Natl Acad Sci USA 106: 14518-23, 2009.

2. Brähler S, Kaistha A, Schmidt J, Wölfle SE, Busch C, Kaistha BP, Kacik M, Hasenau AL, Grgic I, Si H, Bond CT, Adelman JP, Wulff H, deWit C, Hoyer J, Köhler R.

Genetic defizit of SK3 and IK1 channels disrupts the endothelium-derived

hyperpolarizing factor vasodilator pathway and causes hypertension.

Circulation 119: 2323-32, 2009.                    

3. Hartmannsgruber V, Heyken WT, Kacik M, Kaistha A, Grgic I, Harteneck C, Liedtke W, Hoyer J, Kohler R. Arterial response to shear stress critically depends on endothelial TRPV4 expression.

PLoS one. 2007 Sep 5; 2(9):e827.                                                                    

4. Si H, Heyken WT, Wolfle SE, Tysiac M, Schubert R, Grgic I, Vilianovich L, Giebing G, Maier T, Gross V, Bader M, de Wit C, Hoyer J, Köhler R. Impaired endothelium-derived hyperpolarizing factor-mediated dilations and increased blood pressure in mice deficient of the intermediate-conductance Ca²⁺-activated K⁺ channel.

Circ Res 99: 537-544, 2006.                                                                                                                        

5. Köhler R, Heyken WT, Heinau P, Schubert R, Si H, Kacik M, Busch C, Grgic I, Maier T, Hoyer J. Evidence for a functional role of endothelial transient receptor potential V4 in shear stress-induced vasodilatation.

Arterioscler Thromb Vasc Biol 26:1495-502, 2006.