Early life stress (ELS) has long been acknowledged as a major contributor to increased risk for cardiovascular disease in adulthood. Recent epidemiological studies suggest that ELS, as defined by socio- economic status, childhood abuse, or neglect, strongly predicts the increased risk for metabolic syndrome and cardiovascular disease. The incidence of vascular disease in the United States is growing with the increase in childhood obesity and diabetes; however it remains unclear whether adverse early life events have a direct impact on the development of vascular disease. The proposed research plan will elucidate the epigenetic mechanisms by which ELS induces adult endothelial dysfunction in a mouse model. Maternal separation with early weaning (MSEW), a chronic behavioral stress model of ELS, consisted of separating litters from the dams for 4 hours/day from postnatal day (P) 2 to 5, and 8 hours/day from P6 to 17, and weaning at P17. Control litters remained undisturbed until weaning on P21. MSEW did not have any effect on overall body weight (P2-P84). Experiments were then conducted on these mice at 12 weeks of age. Preliminary data reveal that adult MSEW mice have endothelial dysfunction in conduit arteries that is dependent on reactive oxygen species and NADPH oxidase. Also, gene expression of histone deacetylase (HDAC) 1, 6 and 9 are upregulated in the thoracic aortas of adult MSEW mice. HDACs play an important role in endothelial and vascular smooth muscle development. HDAC inhibition reduces vascular pathologies, but little is known of the role of specific HDACs in vascular function. The overall goal of this fellowship proposal is to identify HDAC-dependent mechanisms of ELS-induced endothelial dysfunction and vascular pathology in order to define novel pathways of early diagnosis and intervention of vascular disease. We will utilize both in vivo and ex vivo pharmacological and genetic approaches in the following aims:
Aim 1) To test the hypothesis that ELS-induced endothelial dysfunction is mediated through increased HDAC and/or NOX expression and/or activity; and, Aim 2) To test the hypothesis that ELS induces an HDAC-mediated pro-inflammatory vascular phenotype. New investigations into how epigenetic mechanisms, especially HDACs, regulate vascular function offer an innovative direction for therapies.

Public Health Relevance

Adverse early life events have long been acknowledged as a major contributor to increased risk of vascular disease in adulthood in humans. Using a mouse model of early life stress; we propose to demonstrate that histone deacetylases are a mechanism by which early life stress causes adult vascular dysfunction. Elucidation of the mechanisms by which early life stress mediates adult vascular dysfunction will lead to the development of new therapies for the prevention and intervention of vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32HL116145-03
Application #
8838890
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2014-06-10
Project End
2015-01-15
Budget Start
2014-06-10
Budget End
2015-01-15
Support Year
Fiscal Year
2014
Total Cost
$30,019
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Ho, Dao H (2014) Transgenerational epigenetics: the role of maternal effects in cardiovascular development. Integr Comp Biol 54:43-51
Hyndman, Kelly A; Ho, Dao H; Sega, Martiana F et al. (2014) Histone deacetylase 1 reduces NO production in endothelial cells via lysine deacetylation of NO synthase 3. Am J Physiol Heart Circ Physiol 307:H803-9