<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The role of Smad signaling in maintaining\r\nhemodynamic homeostasis"^^ . "In the present study, I have investigated the cellular molecular and mechanisms regulated by\r\nthe crosstalk between fluid shear stress (FSS) and canonical BMP9/10 signaling pathway,\r\nwhose dysregulation leads to the formation of arteriovenous malformations (AVMs), a\r\npathogenic feature of dysfunctional SMAD4 signaling in endothelial cells (ECs).\r\nInterestingly, in the first part of my study, I found that BMP9/10 signaling pathway through\r\nSMAD4 acts upstream of FSS to restrict FSS-mediated KLF4 induction that tempers the\r\ndownstream Akt activation. And this mechanism is required to maintain EC quiescence and\r\nvascular homeostasis. Thus, upon loss of Smad4 in the ECs two pools of PI3K/Akt\r\nhyperactivation occur: one through transcriptional de-repression of casein kinase (CK2) and\r\nresultant inactivation of PTEN and the second one that is specific to the high-flow AVMs\r\nthrough upregulation of KLF4 driving an increase in the receptor tyrosine kinase, TIE2\r\nexpression that further exacerbates PI3K/Akt signaling activation. These findings highlight the\r\nrole of RTKs other than the well-known VEGFRs in regulating EC mechano-transduction\r\nsignaling events.\r\nIn the second part of my study I was interested in identifying the KLF4-TIE2-Akt upstream\r\nregulatory mechanisms governed by SMAD4 signaling. Interestingly, I identified another RTK,\r\nKIT, that independently of its ligand stem cell factor (SCF) acts upstream of KLF4 and Akt\r\nactivation. I identified that KIT is regulated by the BMP9/10-FSS crosstalk and furthermore\r\nSMAD4 signaling is required for FSS mediated KIT downregulation irrespective of FSS\r\nmagnitude. Thus, is Smad4 LOF ECs, KIT expression is upregulated and mediated excessive\r\nERK5 activation, an upstream event that regulates KLF4 induction upon FSS. Increased KitErk5 pathway was further validated in vivo in neonatal retinas with EC specific Smad4\r\ndepletion. KIT was found also within the AVMs in HHT patient biopsies. Lastly, the inhibition\r\nof Kit using a selective inhibitor was able to rescue AVM formation in mouse retinas, providing\r\nevidence that targeting RTKs can potentially mitigate AVM development. These findings\r\noutline a complex signaling network involving SMAD4, PI3K/AKT, KIT, ERK5, and KLF4,\r\nrevealing RTKs as key modulators of endothelial responses to FSS and AVM pathology. These\r\nresults suggest that RTKs, particularly KIT and TIE2, play a crucial role in the pathogenesis of\r\nAVMs and highlight their potential as therapeutic targets for treating AVM-related vascular\r\nabnormalities."^^ . "2025" . . . . . . . "Johannes"^^ . "Gahn"^^ . "Johannes Gahn"^^ . . . . . . "The role of Smad signaling in maintaining\r\nhemodynamic homeostasis (PDF)"^^ . . . "Corrigendum_Thesis-merged_2.pdf"^^ . . . "The role of Smad signaling in maintaining\r\nhemodynamic homeostasis (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "The role of Smad signaling in maintaining\r\nhemodynamic homeostasis (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "The role of Smad signaling in maintaining\r\nhemodynamic homeostasis (Other)"^^ . . . . . . "preview.jpg"^^ . . . "The role of Smad signaling in maintaining\r\nhemodynamic homeostasis (Other)"^^ . . . . . . "medium.jpg"^^ . . . "The role of Smad signaling in maintaining\r\nhemodynamic homeostasis (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #36742 \n\nThe role of Smad signaling in maintaining \nhemodynamic homeostasis\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . .