Opposing actions of intact and N-terminal fragments of the human prolactingrowth hormone family members on angiogenesis: An efficient mechanism for the regulation of angiogenesis

Angiogenesis, the process of development of a new microvasculature, is regu lated by a balance of positive and negative factors. We show both in vivo a nd in vitro that the members of the human prolactin/growth hormone family, i.e., human prolactin, human growth hormone, human placental lactogen, and human growth hormone variant are angiogenic whereas their respective 16-kDa N-terminal fragments are antiangiogenic. The opposite actions are regulate d in part via activation or inhibition of mitogen-activated protein kinase signaling pathway. In addition, the N-terminal fragments stimulate expressi on of type 1 plasminogen activator inhibitor whereas the intact molecules h ave no effect, an observation consistent with the fragments acting via sepa rate receptors. The concept that a single molecule encodes both angiogenic and antiangiogenic peptides represents an efficient model for regulating th e balance of positive and negative factors controlling angiogenesis. This h ypothesis has potential physiological importance far the control of the vas cular connection between the fetal and maternal circulations in the placent a, where human prolactin, human placental lactogen, and human growth hormon e variant are expressed.