<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Endothelial Smad6 and Smad7 harmonize\r\nblood vessel development and tumor progression"^^ . "Functional maturation of an organotypic blood vessel system and maintenance of vascular\r\nquiescence throughout life are features of health and longevity. During vascular development and\r\nangiogenesis, endothelial cells (EC) are responsive to stimuli and proliferate but once blood vessels\r\nmature, they transition into an actively maintained quiescent state characterized by diminished\r\nsignaling response and proliferative activity. Moreover, EC quiescence is not a one-way street of cell\r\nfate but a transient state and it is still not deciphered what molecular programs are critical for its\r\nacquisition and long-term maintenance. To investigate the mechanisms by which EC acquire and\r\nactively maintain their quiescent resting state, Schlereth et al. performed genome-wide epigenetic\r\nand transcriptomic screens of continuous lung EC in newborn and adult mice. Here, TGFβ signaling,\r\nand the inhibitors Smad6 and Smad7, were most prominently regulated. The TGFβ superfamily is\r\nimperative for facilitating vascular development and endothelial cell fate but its role in maturation\r\nand adult homeostasis is only recently emerging. Notably, the unique integration of TGFβ and BMP-\r\nmediated signaling by the intracellular inhibitors Smad6 and Smad7 over vascular development,\r\nmaturation and quiescence is less well established. By deleting endothelial Smad6 and Smad7 at\r\ndifferent developmental stages up until adult homeostasis, I show that embryonic deletion in\r\nSmad6IECKO mice led to widespread hemorrhages and lethality with moderate penetrance by E18.5.\r\nPostnatal deletion of endothelial Smad6 did not affect retinal angiogenesis but led to increased\r\npathological neovascularization during oxygen-induced retinopathy (OIR). In contrast, Smad7IECKO\r\nmice after embryonic deletion were viable and postnatal loss of endothelial Smad7 impaired retinal\r\nangiogenesis. Combined embryonic deletion of endothelial Smad6 and Smad7 led to lethality with\r\nhigh penetrance before E13.5 and postnatal deletion phenocopied impaired retinal angiogenesis in\r\nSmad7IECKO mice. By challenging adult Smad6- and Smad7IECKO mice with two tumor models (LLC\r\nand B16F10) I found endothelial Smad6 and Smad7 to differentially affect tumor size and survival.\r\nLoss of endothelial Smad6 led to increased tumor size and higher survival during metastasis. Loss of\r\nendothelial Smad7 led to decreased tumor size and lower survival in metastasis. Interestingly, loss of\r\nendothelial Smad6 and Smad7 negated the effects from single deletion. Taken together, I found that\r\nSmad6 and Smad7 differentially regulate physiological and pathological angiogenesis but only have a\r\nnuanced or perhaps dispensable role in vascular quiescence. Preliminary data also suggests\r\nendothelial Smad6 and Smad7 may discreetly regulate primary tumor growth and metastatic\r\ndissemination."^^ . "2024" . . . . . . . "Dimitri"^^ . "Kasakovski"^^ . "Dimitri Kasakovski"^^ . . . . . . "Endothelial Smad6 and Smad7 harmonize\r\nblood vessel development and tumor progression (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "Endothelial Smad6 and Smad7 harmonize\r\nblood vessel development and tumor progression (PDF)"^^ . . . "Kasakovski_DoctoralThesis_2024_correction_final.pdf"^^ . . . "Endothelial Smad6 and Smad7 harmonize\r\nblood vessel development and tumor progression (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "Endothelial Smad6 and Smad7 harmonize\r\nblood vessel development and tumor progression (Other)"^^ . . . . . . "preview.jpg"^^ . . . "Endothelial Smad6 and Smad7 harmonize\r\nblood vessel development and tumor progression (Other)"^^ . . . . . . "medium.jpg"^^ . . . "Endothelial Smad6 and Smad7 harmonize\r\nblood vessel development and tumor progression (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #35009 \n\nEndothelial Smad6 and Smad7 harmonize \nblood vessel development and tumor progression\n\n" . "text/html" . . . "500 Naturwissenschaften und Mathematik"@de . "500 Natural sciences and mathematics"@en . .