The long-term goal of this project is to understand the mechanisms underlying cardiac function and coronary vascular growth of the fetus. The overall hypothesis we wish to test is that coronary angiogenesis in the anemic fetus results in an increase in vascular permeability and cardiac lymph flow and an increase in coronary conductance that persists into adulthood.
Aim (1) To determine if cardiac lymph flow is increased we will measure left ventricular lymph flow in anemic and non-anemic fetal sheep. To test if lymph flow is necessary to maintain ventricular function we will determine if volume loading or obstruction of left ventricular cardiac lymphatic flow results in a decrease in the peak rate of left ventricular pressure increase (dP/dt). We will also measure protein and mRNA levels of aquaporin-1 to determine if there is increased expression of water channels during anemia.
Aim (2) To determine if there are differences in the role of nitric oxide in flow induced versus hypoxic (anemia) induced changes in coronary conductance we will measure coronary conductance before and after chronic anemia or chronic adenosine infusion in the presence and absence of the nitric oxide blocker L-NAME.
Aim (3) To determine if an increase in coronary conductance that develops in the fetal period persists in the young adult, we will measure coronary conductance in 8 month old sheep made anemic as fetuses as well as in non anemic controls. We will also measure coronary conductance in a murine model of fetal anemia.
Aim (4) We will measure coronary conductance before and after injection of recombinant vascular endothelial growth factor in the proximal circumflex coronary artery to determine if coronary conductance can be increased by local injection of a growth factor. These studies will extend the understanding of the long-term effects of coronary vascular growth in the fetus.
