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Abstract

Functional maturation of an organotypic blood vessel system and maintenance of vascular quiescence throughout life are features of health and longevity. During vascular development and angiogenesis, endothelial cells (EC) are responsive to stimuli and proliferate but once blood vessels mature, they transition into an actively maintained quiescent state characterized by diminished signaling response and proliferative activity. Moreover, EC quiescence is not a one-way street of cell fate but a transient state and it is still not deciphered what molecular programs are critical for its acquisition and long-term maintenance. To investigate the mechanisms by which EC acquire and actively maintain their quiescent resting state, Schlereth et al. performed genome-wide epigenetic and transcriptomic screens of continuous lung EC in newborn and adult mice. Here, TGFβ signaling, and the inhibitors Smad6 and Smad7, were most prominently regulated. The TGFβ superfamily is imperative for facilitating vascular development and endothelial cell fate but its role in maturation and adult homeostasis is only recently emerging. Notably, the unique integration of TGFβ and BMP- mediated signaling by the intracellular inhibitors Smad6 and Smad7 over vascular development, maturation and quiescence is less well established. By deleting endothelial Smad6 and Smad7 at different developmental stages up until adult homeostasis, I show that embryonic deletion in Smad6IECKO mice led to widespread hemorrhages and lethality with moderate penetrance by E18.5. Postnatal deletion of endothelial Smad6 did not affect retinal angiogenesis but led to increased pathological neovascularization during oxygen-induced retinopathy (OIR). In contrast, Smad7IECKO mice after embryonic deletion were viable and postnatal loss of endothelial Smad7 impaired retinal angiogenesis. Combined embryonic deletion of endothelial Smad6 and Smad7 led to lethality with high penetrance before E13.5 and postnatal deletion phenocopied impaired retinal angiogenesis in Smad7IECKO mice. By challenging adult Smad6- and Smad7IECKO mice with two tumor models (LLC and B16F10) I found endothelial Smad6 and Smad7 to differentially affect tumor size and survival. Loss of endothelial Smad6 led to increased tumor size and higher survival during metastasis. Loss of endothelial Smad7 led to decreased tumor size and lower survival in metastasis. Interestingly, loss of endothelial Smad6 and Smad7 negated the effects from single deletion. Taken together, I found that Smad6 and Smad7 differentially regulate physiological and pathological angiogenesis but only have a nuanced or perhaps dispensable role in vascular quiescence. Preliminary data also suggests endothelial Smad6 and Smad7 may discreetly regulate primary tumor growth and metastatic dissemination.