Extracellular vesicles are a heterogeneous group of cell-derived membranous structures comprising exosomes and microvesicles, which originate from the endosomal system or which are shed from the plasma membrane, respectively. They are present in biological fluids and are involved in multiple physiological and pathological processes. Extracellular vesicles are now considered as an additional mechanism for intercellular communication, allowing cells to exchange proteins, lipids and genetic material. Knowledge of the cellular processes that govern extracellular vesicle biology is essential to shed light on the physiological and pathological functions of these vesicles as well as on clinical applications involving their use and/or analysis. However, in this expanding field, much remains unknown regarding the origin, biogenesis, secretion, targeting and fate of these vesicles.

Angiogenesis, the process of development of a new microvasculature, is regulated by a balance of positive and negative factors. We show both in vivo and in vitro that the members of the human prolactin͞growth 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 regulated in part via activation or inhibition of mitogen-activated protein kinase signaling pathway. In addition, the N-terminal fragments stimulate expression of type 1 plasminogen activator inhibitor whereas the intact molecules have no effect, an observation consistent with the fragments acting via separate receptors. The concept that a single molecule encodes both angiogenic and antiangiogenic peptides represents an efficient model for regulating the balance of positive and negative factors controlling angiogenesis. This hypothesis has potential physiological importance for the control of the vascular connection between the fetal and maternal circulations in the placenta, where human prolactin, human placental lactogen, and human growth hormone variant are expressed.Prolactin (PRL), growth hormone (GH), and placental lactogen (PL) are homologous protein hormones believed to have arisen from a common ancestral gene (1). PRL participates in the regulation of reproduction, osmoregulation, and immunomodulation (2, 3) whereas GH is involved in regulating growth and morphogenesis (4). Human (h) GHs, unlike other mammalian GHs, bind to the PRL receptor and thus display PRL-like activity; however, hPRL does not bind to the hGH receptor (5). PRL and GH are produced mainly by the anterior pituitary in all vertebrates. PRL is expressed also in lymphocytes and in the decidua (6). The human placenta expresses two structural homologs of hGH, hPL and a variant of hGH (hGH-V) (7). hGH-V rather than pituitary hGH is believed to regulate maternal metabolism during the second half of pregnancy. hPL is somatotropic in fetal tissues and contributes to stimulating mammary cell proliferation (8). Rodent placentas express and secrete several proteins whose biological activities are more PRL-like than GH-like; these include proliferin (PLF) and a proliferin-related peptide (PRP) (9).Members of the PRL͞GH family and derived peptides have been reported to both stimulate and inhibit angiogenesis. PLF expressed during the first half of pregnancy in the mouse is angiogenic whereas PRP expressed later in gestation is antiangiogenic. These findings suggest that PLF and PRP might play a role in initiating and stopping placental neovascularization (9). Human GH was reported to be angiogenic in vitro (10) whereas both bovine and chicken GH were shown to be angiogenic in vivo (11). We have shown that the 16-kDa N-terminal fragments (16K) of rat PRL and hPRL are antiangiogenic both in vitro (12) and in vivo (13). Rat PRL is cleaved by cathepsin D (14) to yield a 16-kDa N-terminal fragment and a 7-kDa C...

nowledge of EV biogenesis pathways and biological activities has grown rapidly in the past decade 1 (Fig. 1a,b). EVs are membrane-enclosed structures that are released into the extracellular milieu by all organisms and cell types studied so far. EVs are a diverse family in which subtypes have been defined based on subcellular origin, size, and composition: endosome-derived vesicles (including multivesicular endosome-derived exosomes with a diameter of 50-150 nm and secretory autophagosome-derived EVs); ectosomes and other microvesicles that bud from the plasma membrane (PM) as small as exosomes or up to several µm in size; midbody remnants released by dividing cells (Box 1); migrasomes trailing behind migrating cells 2,3 ; apoptotic bodies dislodged from