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P1: Crosstalk of ion channels and transcription factors in the vascular wall

Current state of relevant research

Proper communication between the cells in the vascular wall is essential for vessel functions e.g. vascular tone and dilatation, but also for the maintenance of vascular homeostasis on the structural and functional level. This intercellular communication is mediated by numerous signaling molecules e.g. nitric oxide (1), but also molecules that cannot penetrate the cell membrane like cytokines and hormones, which thus, must act through membrane-bound receptors, among them ion-channels (2, 3). Within the cell, these signals are relayed by a multiplicity of pathways, many of which culminate/are integrated on the level of transcription factors leading to adaptive or maladaptive outputs (4). The endothelial cell (EC) layer is critical to vascular homeostasis, which is underscored by the fact that endothelial dysfunction is a hallmark of all major cardiovascular diseases (5).

Preliminary work

Endothelial Ca2+ is a key determinant of endothelial function. We recently demonstrated that Ca2+ influx through TRPV4 (transient receptor potential vanilloid 4) channels on the EC membrane is a key regulator of endothelium-dependent vasodilation (6). The TRPV4 channels on the EC membrane exhibit coupled openings, and this coupling among TRPV4 channels is dependent on AKAP150 (A kinase anchoring protein 150), which anchors protein kinase A and protein kinase C. However, the nature of TRPV4-AKAP150 interaction is unclear. A downregulation of AKAP150 results in lower Ca2+ influx through TRPV4 channels, and loss of endothelial vasodilations in hypertensive mice (7) and high-fat diet fed obese mice (unpublished preliminary data from the Sonkusare lab). A thorough understanding of AKAP150-TRPV4 interaction is therefore necessary for deciphering the pathological mechanisms that are responsible for the loss of endothelial vasodilations in hypertension and other vascular disorders. At the level of signal integration by transcriptional regulatory proteins, we have demonstrated that the transcription factor Grainyhead-like 3 (GRHL3) regulates essential features of endothelial cells, namely migration, apoptosis protection and NO-production (8, 9) . Moreover, we have shown that GRHL3 regulates several ion channels in endothelial cells. In addition, we observed a massive downregulation of GRHL3 in the endothelium of mice fed a high fat diet, an established model for atherosclerosis development, and for the first time expression of GRHL3 also in vascular smooth muscle cells (unpublished work from the exchange phase during the first funding period).

Research objectives of the joint program

This tandem project will provide novel insights into regulatory networks in the vasculature under normal and disease conditions. By studying the cross-talk of membrane-associated signaling elements and effectors on the transcriptional level we will determine how physiological and pathological stimuli modify vascular function through these signaling circuits. The specific, complementary expertise of the partnering laboratories will allow us to pursue experimental approaches that could not be followed by the two laboratories separately.