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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TRPV4 channels, and loss of endothelial vasodilations in hypertensive mice (7) and high-fat diet fed obese mice (unpublished preliminary data from the Sonkusare lab).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.

  1. Zhao, Y., Vanhoutte, P. M., and Leung, S. W. (2015) Vascular nitric oxide: Beyond eNOS. J Pharmacol Sci 129, 83-94
  2. Hill-Eubanks, D. C., Gonzales, A. L., Sonkusare, S. K., and Nelson, M. T. (2014) Vascular TRP channels: performing under pressure and going with the flow. Physiology (Bethesda) 29, 343-360
  3. Sonkusare, S. K., Dalsgaard, T., Bonev, A. D., and Nelson, M. T. (2016) Inward rectifier potassium (Kir2. 1) channels as end‐stage boosters of endothelium‐dependent vasodilators. J Physiol 594, 3271-3285
  4. Kohlgrüber, S., Upadhye, A., Dyballa-Rukes, N., McNamara, C. A., and Altschmied, J. (2017) Regulation of transcription factors by reactive oxygen species and nitric oxide in vascular physiology and pathology. Antioxid Redox Signal doi: 10.1089/ars.2016.6946
  5. Rajendran, P., Rengarajan, T., Thangavel, J., Nishigaki, Y., Sakthisekaran, D., Sethi, G., and Nishigaki, I. (2013) The vascular endothelium and human diseases. Int J Biol Sci 9, 1057-1069
  6. Sonkusare, S. K., Bonev, A. D., Ledoux, J., Liedtke, W., Kotlikoff, M. I., Heppner, T. J., Hill-Eubanks, D. C., and Nelson, M. T. (2012) Elementary Ca2+ signals through endothelial TRPV4 channels regulate vascular function. Science 336, 597-601
  7. Sonkusare, S. K., Dalsgaard, T., Bonev, A. D., Hill-Eubanks, D. C., Kotlikoff, M. I., Scott, J. D., Santana, L. F., and Nelson, M. T. (2014) AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Sci Signal 7, ra66
  8. Guardiola-Serrano, F., Haendeler, J., Lukosz, M., Sturm, K., von Melchner, H., and Altschmied, J. (2008) Gene trapping identifies a putative tumor suppressor and a new inducer of cell migration. Biochem Biophys Res Commun 376, 748-752
  9. Lukosz, M., Mlynek, A., Czypiorski, P., Altschmied, J., and Haendeler, J. (2011) The transcription factor Grainyhead like 3 (GRHL3) affects endothelial cell apoptosis and migration in a NO-dependent manner. Biochem Biophys Res Commun 412, 648-653

 Jander, K.*, Greulich, J.*, Gonnissen, S.*, Ale-Agha, N., Goy, C., Jakobs, P., Farrokh, S., Marziano, C., Sonkusare, S.K., Haendeler, J.§, and Altschmied, J.§ (2021). Extra-nuclear functions of the transcription factor grainyhead-like 3 in the endothelium - interaction with endothelial nitric oxide synthase. Antioxidants (Basel). 10, 428.
*equal contribution, §joint senior authors

Ottolini, M., Hong, K., Cope, E.L., Daneva, Z., DeLalio, L.J., Sokolowski, J.D., Marziano, C., Nguyen, N.Y., Altschmied, J., Haendeler, J., Johnstone, S.R., Kalani, M.Y., Park, M.S., Patel, R.P., Liedtke, W., Isakson, B.E., and Sonkusare, S.K. (2020). Local Peroxynitrite Impairs Endothelial TRPV4 Channels and Elevates Blood Pressure in Obesity. Circulation 141, 1318-1333.

Rosen, J.*, Jakobs, P.*, Ale-Agha, N., Altschmied, J., and Haendeler, J. (2020) Non-canonical functions of telomerase reverse transcriptase - impact on redox homeostasis. Redox Biol. 34, 101543.
*equal contribution

Gonnissen, S.*, Ptok, J.*, Goy, C., Jander, K., Jakobs, P., Eckermann, O., Kaisers, W., von Ameln, F., Timm, J., Ale-Agha, N., Haendeler, J. §, Schaal, H., and Altschmied, J. (2019). High Concentration of Low-Density Lipoprotein Results in Disturbances in Mitochondrial Transcription and Functionality in Endothelial Cells. Oxid Med Cell Longev 2019, 7976382.
*equal contribution, §corresponding author

Spannbrucker, T.*, Ale-Agha, N.*, Goy, C., Dyballa-Rukes, N., Jakobs, P., Jander, K., Altschmied, J., Unfried, K., and Haendeler, J. (2019) Induction of a senescent like phenotype and loss of gap junctional intercellular communication by carbon nanoparticle exposure of lung epithelial cells. Exp Gerontol 117, 106-112.
*equal contribution

Kohlgrüber, S., Upad­hye, A., Dyballa-​Rukes, N., McNamara, C. A., and Altschmied,J. (2017) Regulation of Transcription Factors by Reactive Oxygen Species and Nitric Oxide in Vascular Physiology and Pathology. Antioxid Redox Signal 26, 679-699

Dyballa-​Rukes, N.*, Jakobs, P.*, Eckers, A., Ale-Agha, N., Serbulea, V., Aufenvenne, K., Zschauer, T. C., Rabanter, L. L., Jakob, S., von Ameln, F., Eckermann, O., Leitinger, N., Goy, C., Altschmied, J., and Haendeler, J. (2016) The anti-apoptotic properties of APEX1 in the endothelium require the first twenty amino acids and converge on Thioredoxin-1. Antioxid Redox Signal 26, 616-629
*equal contribution

Zurek, M., Altschmied, J., Kohlgrüber, S., Ale-​Agha, N., and Haen­deler, J. (2016) Role of Telom­erase in the Car­dio­vas­cu­lar Sys­tem. Genes 7, 29

Far­rokh, S., Brillen, A. L., Haen­deler, J., Altschmied, J., and Schaal, H. (2015) Critical regulators of endothelial cell functions: for a change being alternative. Antioxid Redox Signal 22, 1212-1229

Schuler, D., San­sone, R., Freuden­berger, T., Rodriguez-​Mateos, A., Weber, G., Momma, T. Y., Goy, C., Altschmied, J., Haendeler, J., Fischer, J. W., Kelm, M., and Heiss, C. (2014) Measurement of endothelium-dependent vasodilation in mice--brief report. Arterioscler Thromb Vasc Biol 34, 2651-2657

Haen­deler, J., Mlynek, A., Büchner, N., Lukosz, M., Graf, M., Guet­tler, C., Jakob, S., Far­rokh, S., Kunze, K., Goy, C., Guardiola-​Serrano, F., Schaal, H., Cortese-​Krott, M., Dee­nen, R., Kohrer, K., Win­kler, C., and Altschmied, J. (2013) Two iso­forms of Sister-​Of- Mam­malian Grainy­head have op­pos­ing func­tions in en­dothe­lial cells and in vivo. Ar­te­rioscler Thromb Vasc Biol 33, 1639-​1646