Mechanisms regulating angiogenesis underlie seasonal control of pituitary function

Abstract

Seasonal changes in mammalian physiology, such as those affecting reproduction, hibernation, and metabolism, are controlled by pituitary hormones released in response to annual environmental changes. In temperate zones, the primary environmental cue driving seasonal reproductive cycles is the change in day length (i.e., photoperiod), encoded by the pattern of melatonin secretion from the pineal gland. However, although reproduction relies on hypothalamic gonadotrophin-releasing hormone output, and most cells producing reproductive hormones are in the pars distalis (PD) of the pituitary, melatonin receptors are localized in the pars tuberalis (PT), a physically and functionally separate part of the gland. How melatonin in the PT controls the PD is not understood. Here we show that melatonin time-dependently acts on its receptors in the PT to alter splicing of vascular endothelial growth factor (VEGF). Outside the breeding season (BS), angiogenic VEGF-A stimulates vessel growth in the infundibulum, aiding vascular communication among the PT, PD, and brain. This also acts on VEGF receptor 2 (VEGFR2) expressed in PD prolactin-producing cells known to impair gonadotrophin secretion. In contrast, in the BS, melatonin releases antiangiogenic VEGF-Ab from the PT, inhibiting infundibular angiogenesis and diminishing lactotroph (LT) VEGFR2 expression, lifting reproductive axis repression in response to shorter day lengths. The time-dependent, melatonin-induced differential expression of VEGF-A isoforms culminates in alterations in gonadotroph function opposite to those of LTs, with up-regulation and down-regulation of gonadotrophin gene expression during the breeding and nonbreeding seasons, respectively. These results provide a mechanism by which melatonin can control pituitary function in a seasonal manner.

The origins of the circumventricular organs

“…Various developmental signalling pathways are involved in vasculogenesis, and a systematic analysis of whether and how these have been modified in developing CVOs could help establish the mechanisms that distinguish CVOs from other parts of the brain (Roca & Adams, 2007;Mancuso et al 2008;Adams & Eichmann, 2010;Liebner & Plate, 2010). Recently vascularisation in the pars tuberalis of the median eminence was shown to be modulated in a circannual fashion through melatonin-regulated differential splicing of vascular endothelial growth factor (Castle-Miller et al 2017). This fascinating study suggests that CVOs remain dynamic structures throughout life.…”

“…Recently vascularisation in the pars tuberalis of the median eminence was shown to be modulated in a circannual fashion through melatonin‐regulated differential splicing of vascular endothelial growth factor (Castle‐Miller et al. ). This fascinating study suggests that CVOs remain dynamic structures throughout life.…”

Sex-Specific Characteristics of the Microcirculation

“…Thus, not only can a hormone or vasoactive compounds be important in regulating microvascular function, but the rate of change (a spike) can be of importance. This appears to be also the case for vascular endothelial growth factor (VEGF) [8, 10], a potent mediator of permeability. Plasma levels of VEGF are higher in men than women and are correlated with the development of atherosclerosis [62], a disease process shown to occur more frequently in males.…”

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

“…Melatonin is secreted by the pineal gland, which is regulated by dark-light and seasonal cycles in mammals [19]. It acts as an antioxidant by reducing oxidative stress and increasing the activity of antioxidant enzymes in the body [20].…”