Vascular Endothelial Growth Factor and Angiogenesis

Abstract

After the occlusion of a nutritive blood vessel, muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the fate of the ischemic tissue. During the latter phase of tissue healing, the different processes involved in new vessel formation, including angiogenesis, take place and represent an integral component of tissue remodeling, which controls the extent of ischemic injury. Angiogenesis is a complex process requiring the coordinated regulation of many activating and inhibitory pathways in which vascular endothelial growth factor (VEGF)–mediated endothelial cell (EC) migration and proliferation play an important role. VEGF acts, at least in part, through interaction with its VEGF receptor 2, also known as kinase insert domain receptor (KDR) in human or fetal liver kinase 1 (Flk1) in murine. Although the signaling pathways downstream of VEGF-mediated KDR/Flk1 activation have been analyzed in detail, the precise complex biology of this receptor has yet to be defined. Article see p 1712 The X-box binding protein 1 (XBP1) exists as unspliced (XBP1u) and spliced (XBP1s) forms via the action of inositol-requiring enzyme 1α (IRE1α)–mediated unconventional splicing, in which XBP1u facilitates the recruitment of XBP1 mRNA cotranslationally.1 In addition, XBP1s protein level is downregulated by XBP1u through proteasome-mediated degradation.2 XBP1, a stress-inducible transcription factor, constitutes a key signal transducer in the endoplasmic reticulum (ER) stress response. The ER has emerged as a major site of cellular homeostasis, particularly for the unfolded protein response, which has been shown to play a major role in cancer and many other diseases. XBP1 has been identified as a target of ATF6, a major sensor and transducer protein on the ER membrane, …