Thrice‐Weekly Acute Intermittent Hypoxia Induces Vascular Endothelial Growth Factor (VEGF) in Phrenic Motor Neurons

VEGF is a hypoxia sensitive growth factor known to play a critical role in angiogenesis in vertebrates. Recent evidence indicates that VEGF is also expressed in motor neurons where it promotes neuroprotection (Storkebaum et al. Bioessays , 2004). Acute intermittent hypoxia (AIH) elicits respiratory plasticity in phrenic motor neurons and induces the expression of multiple trophic factors, such as brain derived neurotrophic factor (BDNF; Baker‐Herman et al., Nature Neurosci ., 2004; Satriotomo et al. ibid , 2007). Since VEGF and BDNF activate receptor tyrosine kinases and similar intracellular signaling cascades, we wondered if VEGF plays a role in AIH induced respiratory plasticity. To begin investigation of this possibility, we tested the hypotheses that: VEGF is expressed in phrenic motor neurons; and that thrice weekly exposure to AIH (10, 5‐min episodes, 10.5% O 2 , 3x per week, 10 weeks) increases VEGF expression within phrenic motor neurons. Adult, male, Sprague‐Dawley rats received either normoxia, or thrice‐weekly AIH, from 60 to 111 days of age (n=9). Immunohistochemical staining revealed VEGF protein within presumptive motor neurons in the C4 ventral horn. Thrice‐weekly AIH dramatically increased VEGF expression in presumptive phrenic motor neurons. Furthermore, VEGF was not localized in either astrocytes (GFAP positive cells) or microglia (OX 42 positive cells), indicating that its expression is restricted to neurons under these conditions. Motor neuron VEGF expression has the potential to play an important role in respiratory plasticity following intermittent hypoxia. Supported by: NIH HL80209.