The Physiological Function of Endothelin-2 in Mice.

In order to directly explore the physiological function of ET-2, we generated constitutive, tissue-specific and systemically inducible knockout mice. Global ET-2 deficient mice exhibited severe growth retardation and juvenile lethality. Despite normal milk intake, they suffered from an apparent internal starvation characterized by hypoglycemia, ketonemia, and increased expression of starvation-induced genes in liver. Based on its abundant expression in the gut, I hypothesized that intestinal function of ET-2 is essential for the growth and survival of mice. However, unexpectedly, the intestine was morphologically and functionally normal in the global mutant mice. Moreover, intestine-specific ET-2 deficient mice showed no detectable abnormalities in growth and survival. Instead, I observed that colonic ET-2 has a protective role in epithelial cell injury. Global ET-2 knockout mice were profoundly hypothermic, even at ambient temperatures. Despite the severe hypothermia, DIO2 and UCP-1 failed to increase in brown adipose tissue in ET-2 knockouts. Housing these mice in a warm environment significantly extended the median life span. As temperature regulation is controlled by the central nervous system (CNS), I examined the phenotype in neuron-specific ET-2 knockout mice. However, the mutant mice displayed normal core body temperature, suggesting that ET-2 is not playing a role in CNS-regulated body temperature. ET-2 expression is clearly detected in the lung, with a sharp and transient increase soon after birth. The emphysematous structural change, which is associated with an increase of total lung capacity, resulted in chronic hypoxemia, hypercapnia, and increased erythropoietin synthesis. Finally, to rule out effects of ET-2 during embryonic development, I used the Cre-loxP system to delete ET-2 in neonatal and adult mice, and found that these mice fully reproduced the phenotype previously observed in global knockouts. Together, these findings reveal that ET-2 is critical for growth and survival of postnatal mice by playing important roles in energy homeostasis, thermoregulation, and maintenance of lung morphology and function. My studies rule out ET-2 function in the intestine and brain as being responsible for these phenotypes. However, the dramatic effects of the lung are newly discovered as a potential candidate tissue for critical ET-2 action and lung ET-2 function deserves further investigation.