Research

Cardiovascular Development

Hearts with ventricular septal defect

Cardiovascular abnormalities present at birth or manifesting in adulthood can originate during embryogenesis, but the specific cause of many of them remains elusive. Understanding the mechanisms controlling development of the cardiovascular system is essential for uncovering the origin of disease. Epigenetic regulators of gene expression have emerged as essential orchestrators of developmental pathways, but we have only started to understand their functions in the cardiovascular system. Our lab is investigating how epigenetic regulators, including histone modifiers, chromatin remodelers and organizers of the genome’s three-dimensional structure, control development of cardiac and vascular progenitor cells and their descendants.

Publications

The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells. Roy AR, Ahmed A, DiStefano PV, Chi L, Khyzha N, Galjart N, Wilson MD, Fish JE, Delgado-Olguín P*. J Biol Chem. 2018 Jun 1;293(22):8449-8461. doi: 10.1074/jbc.M117.814699

Ezh2-mediated repression of a transcriptional pathway upstream of Mmp9 maintains integrity of the developing vasculature. Delgado-Olguín P*, Dang LT, He D, Thomas S, Chi L, Sukonnik T, Khyzha N, Dobenecker MW, Fish JE, Bruneau BG. Development. 2014 Dec;141(23):4610-7. doi: 10.1242/dev.112607

Expression of NOL1/NOP2/sun domain (Nsun) RNA methyltransferase family genes in early mouse embryogenesis. Chi L, Delgado-Olguín P*. Gene Expr Patterns. 2013 Dec;13(8):319-27. doi: 10.1016/j.gep.2013.06.003

Embryonic Programming of Heart Disease

Heart development in a mouse embryo

The risk of developing heart disease at an early age is higher in people if they were exposed to maternal obesity during fetal development. Because rates of obesity in women have increased over the years, and because of factors that stress the heart, children as young as 12 years old are at an increasing risk of early-onset heart disease. We do not yet understand how obesity during pregnancy makes the heart prone to disease. Once we do, we can use this knowledge to prevent heart disease in future generations. We are investigating the connection between maternal obesity and heart disease in the offspring. We are focused on uncovering the earliest effects of obesity during pregnancy on gene expression and the pathways that sensitize the heart to adult-onset disease.

Publications

Maternal obesity alters cardiac progenitor gene expression and programs adult-onset heart disease susceptibility. Ahmed A., Liang M., Chi L., Zhou Y. Q., Sled J. G., Wilson M. D. Delgado-Olguin P*. Molecular Metabolism. 2021 Jan;43:101116. doi: 10.1016/j.molmet.2020.101116

Embryonic programming of heart disease in response to obesity during pregnancy. Ahmed A, Delgado-Olguin P*. Biochim Biophys Acta Mol Basis Dis. 2019 Feb 10;pii: S0925-4439(19)30040-7. doi: 10.1016/j.bbadis.2019.01.028

Placental Vasculature Maturation

Placenta

The placenta is a transitory organ essential for pregnancy and fetal development. To comply with nutritional demands of the growing fetus, the placenta transitions from a phase known as the developmental phase to a maturation phase. During maturation, the placental vasculature expands by elongation of the blood vessels. Abnormal maturation of the vasculature reduces placental function leading to restricted fetal growth and programming negative effects on the cardiovascular system’s health after birth. Our lab is investigating the cellular and molecular mechanisms that promote maturation of the placental vasculature. This knowledge will be leveraged towards strategies to prevent the negative effects of placental dysfunction on the postnatal cardiovascular system.

Publications

G9a controls placental vascular maturation by activating the Notch Pathway. Chi L, Ahmed A, Roy AR, Vuong S, Cahill LS, Caporiccio L, Sled JG, Caniggia I, Wilson MD, Delgado-Olguin P*. Development. 2017 Jun 1;144(11):1976-1987. doi: 10.1242/dev.148916.

Journal highlight – Growing a labyrinth with G9a

Interview by THE NODE – The people behind the papers: Lijun Chi and Paul Delgado-Olguin

Cardiomyopathy

Diseases of the heart muscle, or cardiomyopathies, are among the most common causes of death. The most common of these is dilated cardiomyopathy (DCM), which affects as many as 1 in every 250 people. In DCM, the heart’s chambers become enlarged and the heart muscle stretches and thins, eventually reaching a point where the heart can no longer function. Right now, we do not know what causes DCM in about 70% of people who have it. These people are only diagnosed with DCM after their hearts have lost function. Our lab is investigating the events that occur before the heart loses function, and how DCM initiation is regulated. This new information is needed to diagnose DCM early enough to reduce the number of people who die of heart failure. We are studying a unique mouse model whose heart loses function just like people with DCM and dies of fulminant heart failure. Using this model, we discovered that, before it loses function, the heart changes the way it produces energy. We are using mice and cardiomyocytes in vitro to define the early events that lead to loss of heart function, and that control progression of DCM towards fulminant heart failure. The knowledge we gain from this work can be used to find ways to diagnose DCM before the heart loses function and to mitigate the devastating effects of heart failure.

Publications

We are preparing our first manuscript in this research area, stay tuned. In the meantime, please check some of the Principal Investigator’s previous work.