Sexually dimorphic regulation of vascular tone by signaling cross-talk of bioactive lipids

通过生物活性脂质信号串扰对血管张力的性别二态性调节

• 批准号: RGPIN-2021-04398
• 负责人: Hemmings, Denise
• 金额: $ 2.04万
• 依托单位: University of Alberta
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761553
• 关键词: Sexually; dimorphic; regulation; vascular; tone

My group studies factors that cause arteries to become narrower (constricted) versus how they become wider (relaxed). The balance of these opposite responses controls blood pressure. We study two factors called LPA and S1P, which often have similar effects on arteries. However, there are also differences and unique actions of LPA versus S1P. Most researchers study LPA and S1P separately. This misses a critical level of control because each of these factors affects the other. Thus, the responses to LPA and S1P are tightly linked and should be studied together, especially since these interactions differ between men and women. LPA and S1P in the blood interact with cells that line arteries. This sends signals to the underlying muscle cells to relax, which decreases blood pressure. However, when S1P levels rise, the artery lining becomes leaky and allows LPA and S1P in the blood to gain access to the underlying muscle layer. Here, LPA and S1P offset the relaxation by making the muscle constrict, which increases blood pressure. We will study how LPA and S1P work together to control these opposing effects. This is vital to understanding the control of normal blood pressure. Once we understand how normal responses are controlled, we can then begin to discover changes that lead to diseases. We have novel evidence that LPA and S1P are controlled by a factor called SPH, which is also present in the blood. SPH enters cells where it is used to make S1P, which goes back into the blood to control relaxation. We now show that SPH has other effects, one of which is to control the actions of LPA. In turn, LPA controls S1P production. Significantly, SPH levels in blood are about 10 times higher in females compared to males, probably because of the actions of estrogen. The effect of SPH in directing the actions of LPA versus S1P has never been studied. We do not know how this will control artery function in health or in disease and if there will be differences in men and pre- and post-menopausal women. Our proposal will fill these gaps in knowledge. We will study how SPH coordinates the relative effects of LPA and S1P and how this differs between the sexes. My work focuses on understanding how women and men use LPA and S1P to control the function of arteries at different stages of their lives. Understanding these normal responses will also help us to explain why the signs and symptoms of diseases involving the arteries are so different in men and women. Importantly, we will define the normal ways in which SPH, LPA and S1P control responses in arteries and why it is critical to take into account the different responses in women and men. Knowledge from our studies can be applied to tissues other than arteries since LPA and S1P are essential factors in a broad range of responses. Our results should identify new opportunities for the pharmaceutical industry in Canada to develop therapies to treat high blood pressure and heart attacks.

我的团队研究了导致动脉变窄(收缩)的因素与动脉变宽(放松)的原因。这些相反反应的平衡控制着血压。我们研究了两种因素，即LPA和S1P，这两种因素通常对动脉有类似的影响。然而，LPA和S1P也有区别和独特的作用。大多数研究人员将LPA和S1P分开研究。这错过了一个关键的控制水平，因为这些因素中的每一个都会影响另一个因素。因此，对LPA和S1P的反应是紧密联系在一起的，应该一起研究，特别是考虑到这些相互作用在男性和女性之间存在差异。血液中的LPA和S1P与排列动脉的细胞相互作用。这会向潜在的肌肉细胞发出放松的信号，从而降低血压。然而，当S1P水平上升时，动脉内膜变得漏水，使血液中的LPA和S1P能够进入潜在的肌肉层。在这里，LPA和S1P通过使肌肉收缩来抵消放松，从而增加血压。我们将研究LPA和S1P如何协同工作来控制这些相反的影响。这对于理解正常血压的控制至关重要。一旦我们了解了正常反应是如何控制的，我们就可以开始发现导致疾病的变化。我们有新的证据表明，LPA和S1P受一种名为SPH的因子控制，这种因子也存在于血液中。SPH进入细胞，在那里它被用来制造S1P，S1P回到血液中控制放松。我们现在证明SPH还有其他作用，其中之一就是控制LPA的作用。反过来，LPA控制着S1P的生产。值得注意的是，女性血液中的SPH水平大约是男性的10倍，这可能是由于雌激素的作用。SPH在指导LPA与S1P的作用方面的作用从未被研究过。我们不知道这将如何控制健康或疾病中的动脉功能，也不知道男性和绝经前和绝经后的女性是否会有差异。我们的建议将填补这些知识空白。我们将研究SPH如何协调LPA和S1P的相对影响，以及这在性别之间的差异。我的工作重点是了解女性和男性如何在他们生命的不同阶段使用LPA和S1P来控制动脉功能。了解这些正常的反应也将有助于我们解释为什么涉及动脉的疾病的体征和症状在男性和女性之间存在如此大的差异。重要的是，我们将定义SPH、LPA和S1P控制动脉反应的正常方式，以及为什么考虑到女性和男性的不同反应是至关重要的。我们研究的知识可以应用于动脉以外的组织，因为LPA和S1P是广泛反应范围的基本因素。我们的结果应该会为加拿大的制药业找到新的机会，开发治疗高血压和心脏病发作的疗法。