A circadian prelude to regulation of angiogenesis and thrombosis by prolactin and plasminogen activator inhibitor-1

Angiogenesis is key for tissue growth and remodeling both during development, regeneration and under pathological situations such as in cancer. Angiogenesis is tightly regulated by a multitude of both pro-and antiangiogenic factors, the balance of which—known as the angiogenic switch—is determining growth or quiescence of the vasculature. As such, endogenous angiogenesis inhibitors such as angiostatin, endostatin, thrombospondin and 16K prolactin are crucial, especially in adult organisms, for maintaining vascular quiescence and health. Characteristic for endogenous angiogenesis inhibitors is that they are produced by proteolytic cleavage of extra-cellular pro-angiogenic factors but the mechanisms regulating this process as well as the mechanisms by which they inhibit pro-angiogenic signaling remains poorly defined. In large part due to these difficulties, research on endogenous angiogenesis inhibitors have recently lost momentum in favor of efforts towards identifying ways of medically blocking pro-angiogenic factor signaling. However, the rather unsatisfying clinical results gained from inhibition of the main pro-angiogenic signaling pathway; the vascular endothelial growth factor (VEGF)—VEGF receptor axis in several types of cancer, have again raised attention to alternative ways of interfering with this critical aspect of tumor biology.