Endocrine Abstracts

Disturbed brain development and function represents a hallmark of Mct8/Oatp1c1 double knockout (DKO) mice, a well-established mouse model for human MCT8 deficiency. This phenotype can be explained by an impaired TH transport across brain endothelial cells causing a profound brain TH deficiency. Yet, to which extent the brain capillary network formation is compromised in DKO mice has not been elucidated. Here, we examined brain capillary network formation in wildtype, single ko and DKO mice at postnatal day P6, P12, P21 and P120. To this end, we performed immunofluorescence studies using the endothelial cell marker CD31 and quantified vessel network parameters in brain vibratome sections. While measurement of CNS capillary parameters at P6 revealed a similar vessel network in all experimental groups, quantification of cortical vessel length and branching at P12 unraveled an almost 50% reduction only in DKO mice. Similar defects could also be detected at P21 and P120 in the DKO brain indicating permanent vessel formation impairments. Interestingly, small capillaries, in which under normal conditions Mct8 is preferentially expressed, were found to be the most affected. We also assessed transcript levels of capillary markers by qPCR and observed a significantly reduced CD31 as well as glucose transporter Glut1 expression in DKO mice. Transcript levels of angiogenic factors were also found to be significantly reduced in isolated brain blood vessels of DKO mice compared to controls. As we recently demonstrated a strong improvement of brain maturation in DKO mice upon TH analog Triac treatment, we wondered whether Triac application was also sufficient to restore brain angiogenesis. Indeed, measurement of brain capillary parameters in DKO mice treated with Triac (400 ng/g bw) between P1 and P11 revealed normal vessel parameters already at P12. Further studies are ongoing to define the exact critical time window during which Triac can restore brain angiogenesis in DKO animals. Collectively, our studies disclosed a permanently compromised brain capillary network formation in Mct8/Oatp1c1 deficient mice possibly leading to insufficient nutrient and/or oxygen supply. Moreover, postnatal Triac treatment was sufficient to normalize brain vessel parameters in DKO mice underscoring the relevance of proper TH action in CNS angiogenesis.