Hypoxic stress results in increased expression of vascular endothelial growth factor (VEGF), a known stimulator of angiogenesis. Increases in expression result in both properly folded and misfolded VEGF proteins. Misfolded VEGF is exported from the endoplasmic reticulum (ER) into the cytoplasm and ubiquitinated. (A) Hypoxic stress also stimulates phosphorylation of αB-crystallin (αB). Phosphorylated αB-crystallin binds misfolded, monoubiquitinated VEGF and returns it to the ER, where it is folded correctly and transported to the Golgi apparatus for secretion. Thus, the secretion of VEGF is up-regulated, angiogenesis occurs, and hypoxic stress may be reduced. (B) Properly folded VEGF is still transported to the Golgi and secreted. In the absence of αB-crystallin, misfolded, monoubiquitinated VEGF accumulates in the cytoplasm. Some of this will become polyubiquitinated and degrade. The rest of the misfolded VEGF can aggregate, leading to increased stress on the cell. Because misfolded VEGF cannot be transported back to the ER to be refolded, decreased secretion of VEGF occurs and hypoxic stress continues.