NROSCI BIOSC 1070 MSNBIO 2070 December 7, 2018 Developmental Physiology & Physiology of Aging

Developmental Physiology During the first half of pregnancy, the fetus’ own genetic program is the primary determinant of growth. During the second half of pregnancy, the patterns of growth and development are altered by epigenetic factors: placental hormonal environmental (e.g., maternal nutrition, disease, drugs, altitude) metabolic (e.g., diabetes)

Development of Cardiovascular System Circulation begins at 4th week to provide adequate nutrition to multicellular fetus. Many tissues produce red blood cells in the fetus, including blood vessel endothelium and liver. Many early red blood cells are nucleated. Fetal hemoglobin has a higher affinity for O2 than adult hemoglobin. After ~1 postnatal year, offspring starts synthesizing adult hemoglobin.

Development of Respiratory System Respiratory system development is not complete until near the end of gestation. Thus, premature infants have difficulty in breathing. Surfactant is not present until near the time of birth. Cortisol is a primary trigger for surfactant production. Women expected to deliver at 24-34 weeks are provided steroid therapy to induce surfactant production in the fetus. Together, glucocorticoid therapy and infusion of surfactant into the newborn trachea reduce the incidence of respiratory distress syndrome in premature infants.

Development of Nervous System Spinal cord and brainstem reflexes are largely present by 4 months gestation. Cortical development lags, and requires environmental inputs after birth. Nervous system development is not complete until several years after birth.

Development of Renal System The fetal kidneys begin to secrete urine during the second trimester. Fetal urine constitutes most amniotic fluid. However, transport properties of kidney are not as developed as in the adult. Thus, less water is reabsorbed, posing a dehydration risk. Acid-base control by the kidney is particularly poor in newborns.

Development of GI System In general, the GI system becomes functional near the middle of a normal pregnancy. The fetus consumes amniotic fluid, and excretes a waste product called meconium. However, liver function is diminished until after birth, partly because blood is shunted away from the liver during development via ductus venosus

Development of GI System The delayed development of hepatic function poses many problems for the infant: Bilirubin is not eliminated in bile; jaundice can occur, and in rare cases bilirubin encephalopathy Plasma protein levels drop, which can result in edema (due to retarded absorption by capillaries) Clotting factor levels drop in the blood; limited blood clotting potential Limited potential for gluconeogenesis. Newborn must receive nutrition often to avoid a drop in blood glucose

Metabolic Function: Insulin Insulin is not required for glucose transport by fetal tissues until near the time of birth. However, insulin is an essential growth hormone for the fetus. Hyperglycemia in mothers with untreated Type I diabetes results in a large production of insulin by the fetus. This can result in an increased growth rate. Overstimulation of b-cells by hyperglycemia in utero can result in too much insulin secretion in the newborn, and hypoglycemia. Hyperglycemia and placental transfer of insulin in mothers with Type II diabetes can have the same effect.

Metabolic Function: Insulin-Like Growth Factor Insulin-like growth factors from the fetal liver are necessary to stimulate mitosis and development of the fetus. Unlike in adults, secretion of these growth factors is not regulated by growth hormone. The insulin-like growth factors are even released in anencephalic fetuses with no growth hormone.

Metabolic Function: Thyroid Hormone Thyroid hormone is necessary for normal development, particularly of the nervous system. Prior to development of the hypothalamic-pituitary portal system during the second trimester, the thyroid hormone comes from the mother. Thus, hypothyroid mothers typically have offspring with diminished intellectual capacity. Mothers with autoimmune diseases that affect the thyroid gland pass the problematic antibodies to the fetus Lack of iodine results in diminished thyroid hormone production by both the mother and fetus, and severe cretinism. ~20 million have brain damage due to iodine deficiency during fetal life.

Ductus Arteriosus and Foramen Ovale In the developing fetus, two shunts divert blood away from the lungs. The foramen ovale is a shunt between the left atrium and right atrium. In addition, ductus arteriosus is a blood vessel connecting the pulmonary artery to the proximal descending aorta. Between the two, coupled with the extremely high resistance of the pulmonary circulation, practically no blood enters the lungs.

Ductus Arteriosus and Foramen Ovale Since practically no blood is moving from the lungs to the left atrium, left atrial pressure is extremely low in the fetus. Thus, the pressure gradient favors the movement of blood from the right to the left atrium.

Ductus Arteriosus and Foramen Ovale Pressures in the pulmonary artery and aorta are nearly equal in the fetus, or pressure is slightly higher in the pulmonary artery. This is due to relatively weak contractions of the developing left ventricle, as well as the fact that preload to the left ventricle is relatively low. Thus, blood moves from from the pulmonary artery to the descending aorta through ductus arteriosus.

Ductus Arteriosus and Foramen Ovale The trajectory of blood flow from the inferior vena cava favors movement through foramen ovale into the left atrium. The trajectory of blood flow from the superior vena cava favors movement through the tricuspid valve into the right ventricle, and then through ductus arteriosus to the descending aorta and placenta.

Ductus Arteriosus and Foramen Ovale At birth, the shunts must close immediately to permit the normal circulation to commence. Once the fetus is born and begins to breathe, pulmonary circulatory resistance drops precipitously. Blood thus begins to flow through the pulmonary circulation instead of ductus arteriosus, as resistance in the ductus arteriosus is higher.

Ductus Arteriosus and Foramen Ovale High pO2 after birth causes constriction of the smooth muscle in ductus arteriosus The patency of ductus arteriosus is dependent on prostaglandins that are produced in part by the placenta. The prostaglandins inhibit the contraction of smooth muscle within the wall of ductus arteriosus. The prostaglandin levels drop markedly at birth, causing the ductus to collapse as smooth muscle within contracts.

Development of GI System Ductus venosus, which shunts blood away from the liver, closes within a few hours of birth. The closure of ductus venosus allows portal blood flow through the liver. The mechanisms responsible for closure of ductus venosus are unknown. Failure of closure is rare in humans.

The First Breath Breathing movements start near the end of the 1st trimester. Breathing ceases just before labor for an unknown reason. In utero, the alveoli and airways are filled with fluid. Labor induces increases in catecholamines and arginine vasopressin, which cause resorption of the fluid. Fluid is also forced out of the lungs as the fetus moves through the birth canal. Hypoxia and hypercapnia are the main triggers for the first breath. The first breath induces changes in cardiovascular pressures that are responsible for closure of ductus arteriosus and foramen ovale. The first breath is normally the most difficult inspiration of a lifetime. A considerable negative pressure within the intrapleural space is necessary to overcome the effects of surface tension.

Immunity The placenta actively transports IgG to the fetus, which is essential to ward-off infections of the fetus. Maternal IgA, IgM, and IgE do not cross the placenta. The newborn receives IgA in colostrum and breast milk. IgG falls in the newborn as the antibodies transferred from the mother are eliminated. The infant slowly develops the ability to generate its own antibodies. Some maternal antibodies (e.g., to measles) decrease slower than others (e.g., to pertussis). Vaccination schedules must take this into account.

Physiological Effects of Aging Height declines after adolescence because of compression of the cartilaginous disks between the vertebrae and loss of vertebral bone. A loss of 5% height at age 70 is normal. Lean body mass declines during aging, while overall body mass stays constant or increases. Even athletes have an increase in adipose tissue during aging. There is a loss of muscle fibers during aging. This is partly due to death of motoneurons, which leaves muscle fibers uninnervated, causing their atrophy. Sometimes loss of motoneurons results in axonal sprouting and innervation of many muscle fibers by a particular motoneuron. This can affect the precision of movement.

Physiological Effects of Aging Although men do not exhibit the rapid loss of bone in their 50s that women experience, bone loss in the 60s and 70s in both sexes is similar. Osteoporosis is a concern in both elderly men and women. Articular (joint) cartilage thins and exhibits altered mechanical properties during aging. This plays a role in development of osteoarthritis, which often occurs when bones start rubbing together after cartilage is lost.

Physiological Effects of Aging Aging decreases the compliance of arteries, so systolic pressure becomes higher and diastolic pressure is lower. Overall, there is an increase in MAP, and the increased afterload results in thickening of the left ventricular wall. Aging increases the compliance of veins, so there is more peripheral blood pooling and increased susceptibility for orthostatic hypotension.

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