Peripheral and Central Mechanisms of Neurovascular Dysfunction in Human Depression

人类抑郁症神经血管功能障碍的外周和中枢机制

• 批准号: 9306246
• 负责人: Jody Greaney
• 金额: $ 10.47万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9306246
• 关键词: Adult; Antidepressive Agents; Antioxidants; Area; Attenuated; Biochemical; Biological Availability; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular Physiology; Chronic; Clinical Data; Comorbidity; Data; Depressed mood; Development; Diagnostic; Disease remission; Elements; Evaluation; Female; Follow-Up Studies; Fostering; Functional disorder; Goals; Human; Impairment; In Vitro; Interview; Investigation; Learning; Link; Major Depressive Disorder; Mediating; Mediator of activation protein; Mental Depression; Mentors; Molecular; Nerve; Neuraxis; Neuronal Dysfunction; Neurophysiology - biologic function; Nitric Oxide; Nitric Oxide Synthase; Outcome; Pathogenicity; Peripheral; Pharmacotherapy; Play; Premenopause; Production; Reactive Oxygen Species; Research; Research Personnel; Rodent; Rodent Model; Role; Secondary to; Selective Serotonin Reuptake Inhibitor; Sex Characteristics; Sympathetic Nervous System; System; Techniques; Tissues; Training; Vascular Diseases; Vasodilation; Woman; cardiovascular disorder risk; cardiovascular risk factor; career; clinically relevant; depression model; depressive symptoms; global health; improved; in vivo; indexing; innovation; insight; male; men; neurovascular; new therapeutic target; novel; oxidant stress; vascular endothelial dysfunction

PROJECT SUMMARY Major depressive disorder (MDD) is a major global health concern and is directly linked to the development of cardiovascular disease (CVD). Although a number of factors may contribute, accumulating evidence from humans and rodent models indicates that neurovascular dysfunction plays a pathogenic role in MDD-CVD comorbidity. Reduced nitric oxide (NO) bioavailability has emerged as a key mechanism in depression-induced neurovascular dysfunction; however, the molecular mediators are unclear. Compelling evidence in rodent models suggests depression-induced reductions in NO bioavailability, secondary to increases in oxidant stress, mediate peripheral vascular and central neural dysfunction. However, few studies have directly examined the mechanisms underlying NO-mediated neurovascular dysfunction in otherwise healthy adults with MDD. Interestingly, premenopausal women have lower CVD risk than men, yet are more than twice as likely to suffer from MDD. Although these data strongly suggest sex differences in the pathophysiology of MDD-CVD comorbidity, no investigations have examined potential sex differences in the mechanistic underpinnings of neurovascular dysregulation in MDD. Using an innovative translational human approach that combines molecular and biochemical techniques, a comprehensive assessment of endothelial function (micro- and macro-vascular reactivity) and direct recordings of sympathetic nervous system activity, the goal of the proposed studies is to rigorously examine the mechanism(s) underlying neurovascular dysfunction in otherwise healthy adults with MDD. Accordingly, our overall hypothesis is that oxidant stress–induced dysregulation of NO, both peripherally and centrally, underlies neurovascular dysfunction in MDD, representing a mechanistic link between depressive symptoms and CVD risk. In Specific Aim 1, we will examine the mechanistic role of peripheral NO in mediating vascular dysfunction in men and women with MDD, with emphasis on the role of oxidant stress. In Specific Aim 2, we will examine the sympathoinhibitory role of central NO in adults with MDD, also with specific focus on the role of oxidant stress in contributing to aberrant sympathetic function. Finally, in Specific Aim 3, we will investigate the influence of chronic selective serotonin reuptake inhibitors for the treatment of MDD on peripheral and central NO function. In each aim, we will investigate sex differences in MDD-induced neurovascular dysfunction. The findings have the potential to significantly advance our understanding of the mechanisms of neurovascular dysfunction in MDD and may provide novel therapeutic targets to alleviate CVD risk in depressed adults. These projects will extend the applicant's training in integrative neuro-cardiovascular physiology by allowing her to learn additional techniques, including in vitro biochemical analyses of human vascular tissue and the assessment and evaluation of MDD via diagnostic psychiatric interviews. In summary, these studies have the potential to establish and advance a novel area of clinically relevant research, while simultaneously providing strong mentored training and guided professional development, tailored to transition the PI to independence. In addition, potential follow-up studies have been identified that will be critical elements in the applicant's career progression and will foster her long-term career goal of becoming an independent investigator.

PROJECT SUMMARY Major depressive disorder (MDD) is a major global health concern and is directly linked to the development of cardiovascular disease (CVD). Although a number of factors may contribute, accumulating evidence from humans and rodent models indicates that neurovascular dysfunction plays a pathogenic role in MDD-CVD comorbidity. Reduced nitric oxide (NO) bioavailability has emerged as a key mechanism in depression-induced neurovascular dysfunction; however, the molecular mediators are unclear. Compelling evidence in rodent models suggests depression-induced reductions in NO bioavailability, secondary to increases in oxidant stress, mediate peripheral vascular and central neural dysfunction. However, few studies have directly examined the mechanisms underlying NO-mediated neurovascular dysfunction in otherwise healthy adults with MDD. Interestingly, premenopausal women have lower CVD risk than men, yet are more than twice as likely to suffer from MDD. Although these data strongly suggest sex differences in the pathophysiology of MDD-CVD comorbidity, no investigations have examined potential sex differences in the mechanistic underpinnings of neurovascular dysregulation in MDD. Using an innovative translational human approach that combines molecular and biochemical techniques, a comprehensive assessment of endothelial function (micro- and macro-vascular reactivity) and direct recordings of sympathetic nervous system activity, the goal of the proposed studies is to rigorously examine the mechanism(s) underlying neurovascular dysfunction in otherwise healthy adults with MDD. Accordingly, our overall hypothesis is that oxidant stress–induced dysregulation of NO, both peripherally and centrally, underlies neurovascular dysfunction in MDD, representing a mechanistic link between depressive symptoms and CVD risk. In Specific Aim 1, we will examine the mechanistic role of peripheral NO in mediating vascular dysfunction in men and women with MDD, with emphasis on the role of oxidant stress. In Specific Aim 2, we will examine the sympathoinhibitory role of central NO in adults with MDD, also with specific focus on the role of oxidant stress in contributing to aberrant sympathetic function. Finally, in Specific Aim 3, we will investigate the influence of chronic selective serotonin reuptake inhibitors for the treatment of MDD on peripheral and central NO function. In each aim, we will investigate sex differences in MDD-induced neurovascular dysfunction. The findings have the potential to significantly advance our understanding of the mechanisms of neurovascular dysfunction in MDD and may provide novel therapeutic targets to alleviate CVD risk in depressed adults. These projects will extend the applicant's training in integrative neuro-cardiovascular physiology by allowing her to learn additional techniques, including in vitro biochemical analyses of human vascular tissue and the assessment and evaluation of MDD via diagnostic psychiatric interviews. In summary, these studies have the potential to establish and advance a novel area of clinically relevant research, while simultaneously providing strong mentored training and guided professional development, tailored to transition the PI to independence. In addition, potential follow-up studies have been identified that will be critical elements in the applicant's career progression and will foster her long-term career goal of becoming an independent investigator.