Defective development and microcirculation of intestine in Npr2 mutant mice.

Intractable gastrointestinal (GI) diseases often develop during infancy. Our group previously reported that natriuretic peptide receptor B (NPR-B)-deficient Npr2 ^slw/slw mice exhibit severe intestinal dysfunction, such as stenosis and distention, which resembles the dysfunction observed in Hirschsprung's disease-allied disorders. However, the root cause of intestinal dysfunction and the detailed of pathophysiological condition in the intestine are not yet clear. Here, we report that the intestine of preweaning Npr2 ^slw/slw  mice showed bloodless blood vessels, and nodes were found in the lymphatic vessel. Additionally, the lacteals, smooth muscle, blood vessel, and nerves were barely observed in the villi of preweaning Npr2 ^slw/slw mice. Moreover, intramuscular interstitial cells of Cajal (ICC-IM) were clearly reduced. In contrast, villi and ICC-IM were developed normally in surviving adult Npr2 ^slw/slw mice. However, adult Npr2 ^slw/slw mice exhibited partially hypoplastic blood vessels and an atrophied enteric nervous. Furthermore, adult Npr2 ^slw/slw mice showed markedly reduced white adipose tissue. These findings suggest that the cause of GI dysfunction in preweaning Npr2 ^slw/slw mice is attributed to defective intestinal development with microcirculation disorder. Thus, it is suggested that NPR-B signaling is involved in intestinal development and control of microcirculation and fat metabolism. This report provides new insights into intractable GI diseases, obesity, and NPR-B signaling.