Professor Dino A Giussani

My research is in Fetal and Neonatal Physiology and in Developmental Programming, broad fields of Reproduction. There are three main strands to my research programmes, each of which uses an integrative approach at the whole animal, isolated organ, cellular and molecular levels to ask focused questions on the roles of fetal oxygenation in cardiovascular development.

Fetal brain sparing during hypoxia

A serious problem in pregnancy is reduced oxygen delivery to the unborn child (fetal hypoxia).  Understanding the mechanisms which underpin the fetal defence to hypoxia is therefore fundamental to developing prevention and treatment of adverse outcomes.  In response to hypoxia, the fetus redistributes its cardiac output away from peripheral circulations and towards the brain - the so called brain sparing effect.  We made the discovery that fetal brain-sparing is triggered exclusively by a carotid chemoreflex. While the field understood that the mechanisms driving this cardiovascular defence to hypoxia included neural and endocrine components, my research group also discovered that nitric oxide (NO) and reactive oxygen species (ROS) are involved.  The net fetal brain-sparing response to hypoxia thus represents the balance between neural, endocrine and local redox mechanisms.

Perinatal glucocorticoid therapy and fetal cardiovascular function

The second strand of my research investigates how the fetal defence to hypoxia may be modified by the intrauterine environment, triggering beneficial as well as detrimental consequences. We have shown that the fetal cardiovascular defence to hypoxia matures with advancing gestation together with the prepartum surge in fetal cortisol.  This maturational effect can be mimicked by treating the preterm fetus with exogenous glucocorticoids in human clinical doses.  The law in the UK, Canada, USA and Australia states that women at risk of preterm labour should be treated with exogenous glucocorticoids to accelerate fetal lung maturation.  Obstetric practice worldwide now appreciates that this treatment also accelerates maturation of the fetal cardiovascular system in addition to the fetal lung.

Prenatal hypoxia and developmental programming of cardiovascular disease

Intrauterine growth restriction (IUGR) is one of the greatest killers in obstetrics today.  It is also associated with the developmental programming of heart disease in adulthood. The third strand of my research has pioneered the contribution of chronic fetal hypoxia and oxidative stress to IUGR and the developmental programming of heart disease in complicated pregnancy, giving the UK an international lead in the subject.  We isolated the role of chronic fetal hypoxia in promoting IUGR and a prenatal origin of cardiometabolic disease in animals and in humans.  For instance, in human populations in Bolivia, we have shown that despite greater poverty, Andean ancestry confers graded protection against fetal growth restriction in pregnancy at high altitude.  Most recently, we have made the exciting discovery that the mechanism promoting adverse outcomes in the offspring of hypoxic pregnancy is oxidative stress in the fetal heart and circulation, thereby identifying potential targets for intervention.

Maternal Obesity During Pregnancy and Cardiovascular Health in the Mother and Offspring

Obesity has reached epidemic proportions, including in women of reproductive age. Over half of women in the UK are now obese or overweight during pregnancy. This is of significant concern as obesity during pregnancy not only has detrimental effects on the mother, but also on her children. Evidence derived from human studies and from animal models shows that maternal obesity can markedly increase the risk of heart disease in the offspring, even when young and when the progeny is fed a healthy diet and they themselves do not become obese. This highlights that it is something about exposure of the embryo or fetus to an obesity environment during gestation itself that either triggers a fetal origin of cardiovascular dysfunction and/or increases the risk of heart disease in the adult offspring.  Using a newly developed ovine model, the fourth strand of my research programme is currently investigating the impact of maternal obesity during pregnancy on the cardiovascular physiology of the mother, the fetus, the post-partum mother and the adult offspring.

Collectively, research in the Giussani Lab has: 1) improved the fundamental understanding of the regulation of cardiovascular function in fetal life; 2) delineated a role for oxygen and highland ancestry in controlling fetal growth; 3) identified target therapies to inform obstetric and neonatal clinical practice, 4) informed policy about high-altitude pregnancy.

Collaborators

Professor Sue Ozanne
Professor Abigail Fowden
Professor Anne Ferguson Smith
Professor Anibal Llanos
Professor Graham Burton
Professor Jin Ma
Dr Mike Murphy
Dr Andrew Murray
Dr Emilio Herrera
Dr Bernardo Krause
Dr Catherine Aiken