Hypophysial angiogenesis decodes annual time and underlies physiological adaptation to seasonal changes in the environment

Abstract

Adaptation to annual changes in the environment is controlled by hypophysial hormones. In temperate zones, photoperiod is the primary external cue that regulates annual biological cycles and is translated by the pattern of melatonin secretion acting primarily in the hypophysial pars tuberalis. Angiogenic mechanisms within this tissue contribute to decode the melatonin signal through alternative splicing of the vascular endothelial growth factor A (VEGF-A) gene in both the pars tuberalis and the capillary loops of the infundibulum. The resulting melatonin-evoked differential productions of VEGF-A isoforms will induce seasonal remodeling of the vascular connection between the hypothalamus and hypophysis, and act as paracrine messengers in the pars distalis to generate the required seasonal endocrine response. Specifically, the long melatonin signal in winter upregulates antiangiogenic VEGF-A isoforms, which will reduce the number of vascular loops and the density of VEGF receptors in endocrine and folliculo-stellate (FS) cells, inhibit prolactin secretion, and stimulate FSH. In contrast, the short melatonin signal in summer upregulates proangiogenic VEGF-A isoforms that will increase the number of vascular loops and the density of VEGF receptors in endocrine and FS cells, stimulate prolactin secretion, and suppress FSH. A similar system has been identified in long day seasonal breeders, revealing that this is a conserved mechanism of adaptation across species. Thus, an angiogenesis-based, intrahypophysial system for annual time measurement controls local microvascular plasticity and conveys the photoperiodic signal readout from the melatonin sensitive pars tuberalis to the endocrine cells of the pars distalis to regulate seasonal adaptation to the environment.

Keywords: VEGE-A; angiogenesis; melatonin; pars tuberalis; photoperiod; pituitary gland; prolactin.

Figure 1

Seasonal microvascular remodeling of the ovine hypophysial stalk (a). Endothelial staining of the vascular loops connecting the pars tuberalis with the infundibulum in sheep during the breeding season (BS ‐winter) and non‐BS (NBS ‐summer) (b). Effects of season on the number of vascular loops in the ovine hypophysial stalk. ***p < 0.01. Adapted from Castle‐Miller et al. (2017).

Figure 2

Diagrammatic representation of the structure of the VEGF gene and vascular endothelial growth factor (VEGF‐A) splice variants (a). Structure of the VEGF gene denoting the exon 8 alternative splice sites (b). Proangiogenic (VEGF‐A_xxxa) and antiangiogenic (VEGF‐A_XXXb) families of VEGF‐A isoforms. Adapted with permission from Nowak et al. (2008).

Figure 3

Photoperiodic signal transduction relay underlying hypophysial control of circannual prolactin and gonadotrophin (follicle stimulating hormone ‐FSH) cycles in sheep. Pineal melatonin secretion translates the effects of photoperiod on the seasonal secretion of prolactin and FSH by evoking differential synthesis and release of proangiogeneic vascular endothelial growth factor (VEGF‐A_164/165a) and antiangiogenic (VEGF‐A_164/165b) isoforms in the pars tuberalis and vascular loops of the hypophysial stalk to regulate seasonal physiology (a). In the winter (ovine breeding season ‐BS), the long duration of melatonin exposure that mirrors the long nights at this time of year upregulates VEGF‐A_164/165b, leading to a reduction in angiogenesis and in the density of VEGF receptors in endocrine and folliculo‐stellate (FS) cells of the pars distalis, with suppression of prolactin output, and no inhibition of FSH (b). In summer (ovine non‐BS, NBS), the short duration of melatonin exposure that mirrors the short nights at this time of year upregulates the secretion of VEGF‐A_164/165a, resulting in an increase in angiogenesis and in the density of VEGF receptors in endocrine and FS cells of the pars distalis, with stimulation of prolactin secretion, and inhibition of FSH output. Thus, an angiogenesis‐based intra‐hypophysial system contributes to decode the circannual photoperiod/melatonin signal to regulate the endocrine adaptation to the predictable changes in the environment. From Castle‐Miller et al. (2017).