MPI for Heart and Lung Research
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Project leaders: Dr. Akiko Nakayama, Dr. Shulan Pi, Dr. Elena Dyukova, Dr. Young-June Jin, Dr. Haaglim Cho, Dr. Anna Monori-Kiss

PhD Students: Rui Li, Guozheng Liang, Sabrina Kurz

Technical Assistants: Ulrike Krüger, Claudia Ullmann

Figure "Atherosclerosis development"

Atherosclerosis de­velops in areas of disturbed flow, which induces inflammatory signaling in endothelial cells. In contrast, laminar flow promotes athero­protective signaling.

Fluid shear stress exerted by the flowing blood is crucial for the development of blood vessels but is also one of the major regulators of the vascular tone by inducing nitric oxide (NO) formation in endothelial cells, which relaxes vascular smooth muscle cells. Blood flow is also a key factor in the development of atherosclerosis, which mainly occurs in regions of arteries exposed to disturbances in fluid flow. Some of the endothelial mechanosensing and mechanotransduction mechanisms activated by laminar or disturbed flow to promote atheroprotective or atherogenic signaling have recently been identified. Understanding these fundamental processes provides new insights into the pathophysiology of cardiovascular diseases such as arterial hypertension and atherosclerosis.

Based on the analysis of basic signaling processes mediated by heterotrimeric G-proteins in vascular cells (Wirth et al., 2008; Korhonen et al., 2009, Althoff et al., 2012), we have recently identified some of the upstream mechanosensing and mechanosignaling mechanisms in endothelial cells, which involve the mechanosensitive cation channel Piezo1 and G-protein-coupled receptors (Wang et al., 2015; Wang et al., 2016; Albarrán-Juárez et al., 2018; Iring et al., 2019). Future work will aim at the identification of novel mechanosensitive and mechanotransducing processes in endothelial cells and other vascular cells which are differentially involved in anti-inflammatory (atheroprotective) and pro-inflammatory (atherogenic) signaling induced by laminar and disturbed flow, respectively. This includes the recently identified PKN2-mediated regulation of eNOS by laminar flow (Jin et al., 2021), the laminar flow-induced tenascin-X-mediated inhibition of endothelial-to-mesenchymal transition and atherosclerosis (Liang et al., 2022) as well as the role of PIezo1 in integrating low flow and leukocyte adhesion to promote leukocyte extravasation (Wang et al., 2022). The ultimate goal is to better understand how endothelial dysfunction contributes to vascular diseases in order to identify new approaches to prevent cardiovascular disorders at an earlier stage as it is currently possible.
 

Literature

Wang S, Wang B, Shi Y, Möller T, Stegmeyer RI, Strilic B, Li T, Yuan Z, Wang C, Wettschureck N, Vestweber D, Offermanns S. (2022) Mechanosensation by endothelial PIEZO1 is required for leukocyte diapedesis. Blood 140: 171-183

Liang G, Wang S, Shao J, Jin Y, Xu L, Yan Y, Günther S, Wang L, Offermanns S. (2022) Tenascin-X Mediates Flow-Induced Suppression of EndMT and Atherosclerosis. Circ Res. 130: 1647-1659

Jin YJ, Chennupati R, Li R, Liang G, Wang S, Iring A, Graumann J, Wettschureck N, Offermanns S. (2021) Protein kinase N2 mediates flow-induced eNOS activation and vascular tone regulation. J Clin Invest. 131: e145734

Iring A, Jin YJ, Albarrán-Juárez J, Siragusa M, Wang S, Dancs PT, Nakayama A, Tonack S, Chen M, Künne C, Sokol AM, Günther S, Martínez A, Fleming I, Wettschureck N, Graumann J, Weinstein LS, Offermanns S (2019) Shear stress-induced endothelial adrenomedullin signaling regulates vascular tone and blood pressure. J Clin Invest. 130: 2775-2791

Chennupati R, Wirth A, Favre J, Li R, Bonnavion R, Jin YJ, Wietelmann A, Schweda F, Wettschureck N, Henrion D, Offermanns S. (2019) Myogenic vasoconstriction requires G12/G13 and LARG to maintain local and systemic vascular resistance. Elife 8

Wettschureck N, Strilic B, Offermanns S (2019) Passing the Vascular Barrier: Endothelial Signaling Processes Controlling Extravasation. Physiol. Rev. 99: 1467-1525

Albarrán-Juárez J, Iring A, Wang S, Joseph S, Grimm M, Strilic B, Wettschureck N, Althoff TF, Offermanns S. (2018) Piezo1 and Gq/G11 promote endothelial inflammation depending on flow pattern and integrin activation. J. Exp. Med. 215: 2655-2672

Wang, SP, Chennupati R, Iring A, Kaur H, Wettschureck N, Offermanns S. (2016) Endothelial Piezo1 controls blood pressure by mediating flow-induced ATP release. J. Clin. Invest. 126: 4527-4536

Wang S, Iring A, Strilic B, Albarrán Juárez J, Kaur H, Troidl K, Tonack S, Burbiel JC, Müller CE, Fleming I, Lundberg JO, Wettschureck N, Offermanns S (2015). P2Y2 and Gq/G11 control blood pressure by mediating endothelial mechanotransduction. J. Clin. Invest. 125: 3077-3086

Althoff TF, Albarrán Juárez J, Troidl K, Tang C, Wang S, Wirth A, Takefuji M, Wettschureck N, Offermanns S (2012). Procontractile G-protein-mediated signaling pathways antagonistically regulate smooth muscle differentiation in vascular remodeling. J. Exp. Med. 209: 2277-2290

Korhonen H, Fisslthaler B, Moers A, Wirth A, Habermehl D, Wieland T, Schütz G, Wettschureck N, Fleming I, Offermanns S (2009). Anaphylactic shock depends on endothelial Gq/G11. J Exp Med. 206: 411-420

Wirth A, Benyó Z, Lukasova M, Leutgeb B, Wettschureck N, Gorbey S, Őrsy P, Horváth B, Maser-Gluth C, Greiner E, Lemmer B, Schütz G, Gutkind S, Offermanns S (2008). G12/G13-LARG-mediated signalling in vascular smooth muscle is required for salt-induced hypertension. Nat Med. 14: 64-68