Myc Regulates Embryonic Vascular Permeability and Remodeling

Abstract

Abstract-Previous work has shown that c-Myc is required for adequate vasculogenesis and angiogenesis. To further investigate the contribution of Myc to these processes, we conditionally expressed c-Myc in embryonic endothelial cells using a tetracycline-regulated system. Endothelial Myc overexpression resulted in severe defects in the embryonic vascular system. Myc-expressing embryos undergo widespread edema formation and multiple hemorrhagic lesions. They die between embryonic days 14.5 and 17.5. The changes in vascular permeability are not caused by deficiencies in vascular basement membrane composition or pericyte coverage. However, the overall turnover of endothelial cells is elevated as is revealed by increased levels of both proliferation and apoptosis. Whole-mount immunohistochemical analysis revealed alterations in the architecture of capillary networks. The dermal vasculature of Myc-expressing embryos is characterized by a reduction in vessel branching, which occurs despite upregulation of the proangiogenic factors vascular endothelial growth factor-A and angiopoietin-2. Thus, the net outcome of an excess of vascular endothelial growth factor-A and angiopoietin-2 in the face of an elevated cellular turnover appears to be a defect in vascular integrity. by complex molecular and cellular processes and involves 2 distinct mechanisms. Vasculogenesis is responsible for de novo generation of vessels from angioblasts and occurs during the formation of the primitive vascular plexus in extraembryonic tissues and within the embryo. Angiogenesis subsumes formation of new vascular structures from preexisting vessels by sprouting and intussusception. 1 The immature vascular tree adjusts to changes in blood flow and oxygen demand by remodeling. This involves both new vessel growths by sprouting or intussusception, as well as vessel regression, a process called pruning. These processes result in a hierarchically organized vascular pattern that facilitates directional blood flow. 2 Later phases of vascular development involve the differential recruitment of associated support cells, such as smooth muscle cells and pericytes and the formation of vascular basement membranes. 1 Key molecular regulators of early vascular development are vascular endothelial growth factor (VEGF)-A and its cognate receptors VEGFR-1 and VEGFR-2. Mice with mutations in either VEGF-A or the receptors show severe defects in blood vessel formation and die early in embryogenesis before the establishment of blood circulation. Heterozygous VEGF-A embryos also show a lethal phenotype suggesting that fine-tuned regulation of components of the VEGF/ VEGFR system is essential for correct vascular differentiation. 3 Vascular remodeling and vessel stabilization depend on the angiopoietin (Ang)/Tie pathway. 3 The 2 Tie receptors, Tie1 and Tie2/Tek, encode receptor tyrosine kinases predominantly expressed in endothelial cells. 4 Tie2 expression is detectable starting in angioblasts and throughout development with reduced expression in quiescent endotheli...

tRNA synthetase counteracts c-Myc to develop functional vasculature

“…As mentioned above, c-Myc plays a pivotal role in vascular development by promoting VEGFA expression (Baudino et al, 2002; Kokai et al, 2009). In complex with its partner MAX, c-Myc directly binds to classic or nonclassic E-box sequences on DNA (Blackwell et al, 1993; Kim et al, 2008) and recruits histone acetyltransferase to allow chromatin expansion and activate transcription.…”

“…Importantly, these deformities can be partially rescued by transgenic VEGFA expression (Baudino et al, 2002). On the other hand, endothelial-specific c-Myc overexpression in mice also causes embryonic lethality arising from widespread edema, multiple hemorrhagic lesions and severe defects in the vascular network, accompanied by an elevated level of VEGFA (Kokai et al, 2009). Together, these results suggest that the role of c-Myc in vascular development and in promoting VEGFA expression has to be tightly balanced.…”

Kaempferol inhibits VEGF expression and in vitro angiogenesis through a novel ERK-NFκB-cMyc-p21 pathway

“…Since onco-gene cMyc has been reported to play a role in angiogenesis (Bertl et al, 2006; Kokai et al, 2009), it becomes interesting to see whether cMyc is involved in kaempferol’s regulation on VEGF and whether cMyc is activated by NFκB transcription factor in ovarian cancer cells. Our study found that cMyc is down-regulated by kaempferol treatment concentration-dependently and significantly at both mRNA and protein levels (Figure 6).…”

c-Myc Is Required for Proper Coronary Vascular Formation via Cell- and Gene-Specific Signaling

“…A common link among these genes is their direct or indirect regulation by c-Myc 19 . Previous studies have demonstrated c-Myc’s critical role in angiogenesis during development 9,20,21 and cancer 22,23 , yet its precise role in the heart and individual cellular constituents remains undiscovered despite its gross upregulation and function during cardiac pathology 24,25 . Moreover, most studies have focused on the effect of c-Myc overexpression on angiogenesis, but the consequences of reduced c-Myc levels remain unknown.…”