Oxygen differentially affects the hox proteins Hoxb5 and Hoxa5 altering airway branching and lung vascular formation

Abstract

Hoxb5 and Hoxa5 transcription factor proteins uniquely impact lung morphogenesis at the developmental time point when extremely preterm infants are born. The effect of O 2 exposure (0.4 FiO 2 ) used in preterm infant care on these Hox proteins is unknown. We used ex vivo fetal mouse lung organ cultures to explore the effects of 0.4 FiO 2 on lung airway and vascular formation in the context of Hoxb5 and Hoxa5 expression and regulation. Compared to room air, 48 h (h) 0.4 FiO 2 adversely attenuated airway and microvasculature formation while reducing lung growth and epithelial cell volume, and increasing mesenchymal volume. 0.4 FiO 2 decreased pro-angiogenic Hoxb5 and VEGFR2 while not altering protein levels of angiostatic Hoxa5. Lungs returned to RA after 24 h 0.4FiO 2 had partial structural recovery but remained smaller and less developed. Mesenchymal cell apoptosis increased and proliferation decreased with time in O 2 while epithelial cell proliferation significantly increased. Hoxb5 overexpression led to prominent peri-airway VEGFR2 expression and promoted lung vascular and airway patterning. Hoxa5 overexpression had the opposite effects. We conclude that 0.4 FiO 2 exposure causes a profound loss of airway and lung microvascular development that occurs partially via reduction in pro-angiogenic Hoxb5 while angiostatic Hoxa5 expression is maintained.

miR-129-5p and miR-130a-3p Regulate VEGFR-2 Expression in Sensory and Motor Neurons during Development

“…In accordance with our theory, in 2005 Rhoads et al reported on a reduction of VEGFR-2 at the mRNA and protein level in cells expressing Hoxa5 [59]. Further work by Mujahid et al (2013) and Silfa-Mazara (2014) showed interactions between Hoxa5 and VEGFR-2, whereby the amount of VEGFR-2-positive cells in a fetal lung mouse model was altered by miRNA influence, followed by a reduction in the formation of vascular plexuses around the terminal airways. These findings could be associated with the observed changes in Hoxa5 localization [28].…”

“…One interesting candidate seems to be Hoxa5, which is directly regulated by miR-130a-3p [58]. Hoxa5 is known for its important role during embryonic and fetal development of the CNS as well as for an anti-angiogenic effect inter alia through reduction of VEGFR-2 [59,60]. In the present study we could demonstrate that miR-130a-3p indirectly modulated Kdr expression in primary sensory neurons.…”

Homeobox B5 suppression attenuates proliferation and elevates apoptosis in hepatoma cell lines through ERK/MDM2 signalling

“…Hong et al found that HOXB5 increases cell invasion and migration in human gastric carcinoma by regulating β‐catenin. Additionally, a reduction of HOXB5 in mesenchymal cells reportedly facilitates apoptosis . Interference of HOXB5 causes apoptosis in vagal and trunk neural crest cells of mice .…”

“…Abnormal expression of HOXB5 modulates cell viability and proliferation in various cancers, such as non‐small cell lung cancer, breast cancer, osteosarcoma, retinoblastoma, oral squamous cell carcinoma, and gastric carcinoma . HOXB5 also is a significant regulator of mesenchymal cell apoptosis …”