Maintenance of an adequate coronary blood flow is critical to fetal heart development, as well as to normal development of the fetus itself. During long-term hypoxia, the fetal sheep maintains a high coronary blood flow, but reduces blood flow to most of the rest of the body. We have found no morphological changes in the fetal coronary capillary bed that would explain the maintained high flow. However, we have described a significantly reduced contractile response to KCl and to the thromboxane A2 receptor (TxA2R) agonist U46619 in the left circumflex, left anterior descending and right coronary arteries of long-term hypoxemic fetal sheep. Interestingly, we found no alteration in the relaxation response to adenosine. We hypothesize that calcium entry through the L-type calcium channel and by way of the TxA2R is impaired, and/or that the ability of intracellular calcium to induce contraction is reduced. We will test these hypotheses in fetal sheep that are exposed to high altitude (3820 m) hypoxia for the final 110 days of gestation. Using the fetal left anterior descending coronary artery, we will measure L-type calcium channel density, gain (the intracellular Ca2+ and tension response to KCl), and sensitivity to the antagonist nifedipine. We will measure TxA2R density, agonist affinity, and gain (the intracellular InsP3 response per agonist occupied TxA2 receptor) and intracellular InsP3 receptor density and agonist affinity. We will characterize simultaneously the intracellular calcium and tension responses to TxA2R stimulation with U46619 and will determine the contribution of calcium from the sarcoplasmic reticulum and from influx through L-type calcium channels in the response. We will also examine sarcoplasmic reticulum Ca2+ stores, as well as the role of Rho kinase in modulating the calcium response. Upon completion of the studies, we will have a better understanding of the alteration in fetal coronary artery contractility brought about by exposure to long-term hypoxemia.
| Maruko, Keiko; Stiffel, Virginia M; Gilbert, Raymond D (2009) The effect of long-term hypoxia on tension and intracellular calcium responses following stimulation of the thromboxane A(2) receptor in the left anterior descending coronary artery of fetal sheep. Reprod Sci 16:364-72 |
| Kono, Satoshi; Stiffel, Virginia M; Gilbert, Raymond D (2006) Effects of long-term, high-altitude hypoxia on tension and intracellular calcium responses in coronary arteries of fetal and adult sheep. J Soc Gynecol Investig 13:11-8 |
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