Angiogenic mechanisms underlie seasonal adaptation to a changing environment

血管生成机制是季节性适应不断变化的环境的基础

• 批准号: BB/S003401/1
• 负责人: Domingo Jorge Tortonese
• 金额: $ 65.4万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FS003401%2F1
• 关键词: Angiogenic; mechanisms; underlie; seasonal; adaptation

Adaptive responses to seasonal changes in the environment are a fundamental strategy for survival in species living in temperate zones. The resulting annual rhythms in physiological processes such as reproduction, metabolism, hair and hoof growth, etc., are controlled by seasonal cycles of hormones secreted by the pituitary gland, and synchronised by the predictable changes in day length (photoperiod). Photoperiodic information is decoded by the pattern of melatonin secreted by the pineal gland. As melatonin is only produced at night, the duration of the nocturnal peak tells the animal how long the night is; thus, the night production of melatonin is much longer during the winter than during the summer. Melatonin exerts its effects on the pituitary gland, in a region called the pars tuberalis (PT). The PT is strategically located between the brain and the rest of the pituitary and has been regarded as the site of the annual biological clock. However, most of the hormones that control seasonal changes in physiology are produced by the pars distalis (PD), an anatomically different region of the pituitary. Therefore, an intra-pituitary system of communication, to convey photoperiodic signals from the melatonin sensitive PT to the endocrine cells of the PD, is fundamental to ensure seasonal adaptation to the environment. We have recently shown that in sheep the blood vessels connecting the PT with the PD undergo seasonal remodelling in response to photoperiod. Vascular remodelling is governed by vascular endothelial growth factor (VEGF-A), a protein that controls the structure and permeability of blood vessels. Our previous work demonstrated that two forms of VEGF-A are produced, one that stimulates blood vessel growth, referred to as the pro-angiogenic form, and another one that inhibits it, referred to as the anti-angiogenic form. These two forms result from a slight modification of the same gene product and compete with each other in the target cells. We have revealed that the melatonin sensitive cells of the PT also produce VEGF-A, and that the duration of the melatonin signal controls the differential production of the two VEGF-A forms. In the summer, the short duration of melatonin stimulates the pro-angiogenic VEGF-A form, leading to an increase in the number of blood vessels and stimulation of prolactin (a hormone that regulates hair growth) from the PD; in contrast, in the winter, the long duration of melatonin stimulates the anti-angiogenic VEGF-A form, leading to a decrease in blood vessels and suppression of prolactin secretion. Additional pilot data have shown that a similar system operates in the equine pituitary, providing preliminary evidence that the melatonin-induced VEGF dependent control of pituitary function is a conserved mechanism of adaptation across species. How the duration of melatonin exposure can modify VEGF-A gene expression to produce pro- or anti-angiogenic variants is not known. The differential VEGF-A gene outputs result from a process known as alternative splicing, and depends on the actions of a factor called SRSF6. In rodents, alternative splicing of other genes can be regulated by external cues such as feeding/fasting, and is associated to the daily (circadian) biological clock machinery. Because melatonin is a major regulator of the circadian clockwork within the PT, a link between this daily time measuring system, the differential production of VEGF-A forms as seasonal time decoding messengers, and their regulation by another external cue, i.e. photoperiod, can be envisaged. Here, we will investigate how melatonin generates differential production of VEGF-A forms to induce adaptation to a changing environment using animal models that reproduce at opposite times of the year, and a variety of laboratory techniques and technical strategies which, when combined, will allow us to gain an in-depth understanding of this novel mechanism of adjustment that has evolved to maximise species survival.

对环境季节变化的适应性反应是生活在温带的物种生存的基本策略。由此产生的生殖、新陈代谢、毛发和蹄生长等生理过程的年度节律，受脑下垂体分泌的激素的季节性周期控制，并与可预测的日长变化（光周期）同步。光周期信息是由松果体分泌的褪黑激素模式解码的。由于褪黑激素只在夜间产生，夜间峰值的持续时间告诉动物夜晚有多长;因此，冬季的褪黑激素夜间产生时间比夏季长得多。褪黑激素对脑垂体的一个叫做结节部（PT）的区域发挥作用。PT位于大脑和垂体其他部分之间，被认为是年度生物钟的所在地。然而，大多数控制季节性生理变化的激素是由垂体远侧部（PD）产生的，这是垂体的一个解剖学上不同的区域。因此，脑垂体内的通信系统，从褪黑激素敏感的PT传递光周期信号到PD的内分泌细胞，是确保季节性适应环境的基础。我们最近表明，在绵羊的血管连接PT与PD进行季节性重塑，以响应光周期。血管重塑由血管内皮生长因子（VEGF-A）控制，VEGF-A是一种控制血管结构和渗透性的蛋白质。我们以前的工作表明，产生了两种形式的VEGF-A，一种刺激血管生长，称为促血管生成形式，另一种抑制它，称为抗血管生成形式。这两种形式是由相同基因产物的轻微修饰引起的，并在靶细胞中相互竞争。我们已经揭示了PT的褪黑激素敏感细胞也产生VEGF-A，并且褪黑激素信号的持续时间控制两种VEGF-A形式的差异产生。在夏季，褪黑激素的短持续时间刺激促血管生成的VEGF-A形式，导致血管数量增加并刺激来自PD的催乳素（一种调节毛发生长的激素）;相反，在冬季，褪黑激素的长持续时间刺激抗血管生成的VEGF-A形式，导致血管减少并抑制催乳素分泌。额外的试点数据表明，一个类似的系统在马的垂体，提供了初步证据表明，褪黑激素诱导的VEGF依赖性控制垂体功能是一个保守的适应跨物种的机制。褪黑激素暴露的持续时间如何改变VEGF-A基因表达以产生促血管生成或抗血管生成变体尚不清楚。差异VEGF-A基因输出是由一种称为选择性剪接的过程引起的，并且取决于一种称为SRSF 6的因子的作用。在啮齿类动物中，其他基因的选择性剪接可以通过外部线索（如进食/禁食）进行调节，并与日常（昼夜节律）生物钟机制相关。由于褪黑激素是PT内昼夜节律时钟的主要调节剂，因此可以设想这种每日时间测量系统、VEGF-A的差异产生形式（作为季节性时间解码信使）与它们通过另一种外部线索（即光周期）的调节之间的联系。在这里，我们将研究褪黑激素如何产生VEGF-A形式的差异生产，以诱导适应不断变化的环境，使用在一年中相反时间繁殖的动物模型，以及各种实验室技术和技术策略，当它们结合在一起时，将使我们能够深入了解这种新的调整机制，这种机制已经进化到最大限度地提高物种生存率。

项目成果

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

• DOI: 10.1002/jez.2639
• 发表时间: 2022-12
• 期刊: JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY
• 影响因子: 2.8
• 作者: Tortonese, Domingo J.