Morphological and functional alterations in the aorta of the chronically hypoxic fetal rat.

In human pregnancy, reduced placental perfusion has been associated with fetal aortic thickening. However, the relative contributions of fetal undernutrition versus fetal underoxygenation to triggering alterations in fetal cardiovascular development remain uncertain. Here, we isolate the effects of chronic fetal hypoxia on fetal cardiovascular development in a specific rodent model of chronic fetal hypoxia independent of changes in nutrition during pregnancy. Pregnant rats were housed under normoxic (21% O(2)) or hypoxic (13% O(2)) conditions from day 6 to day 20 of gestation. At day 20, pups and placentas were weighed. Fetal thoraces were fixed for quantitative histological analysis of the aorta. In a separate group, fetal aortic reactivity was assessed via in vitro wire myography. The experiments controlled for sex and within-litter variation. Placental weight was increased and fetal weight maintained in hypoxic pregnancy. Hypoxic pregnancy led to a 176% increment in wall thickness and a 170% increment in the wall-to-lumen area ratio of the fetal aorta. Fetal aortic vascular reactivity was markedly impaired, showing reduced constrictor and relaxant responsiveness in hypoxic pregnancy. Chronic developmental hypoxia independent of changes in nutrition has profound effects on the morphology and function of the fetal aorta in a mammalian species.

Gfi1 expression is controlled by five distinct regulatory regions spread over 100 kilobases, with Scl/Tal1, Gata2, PU.1, Erg, Meis1, and Runx1 acting as upstream regulators in early hematopoietic cells.

The growth factor independence 1 (Gfi1) gene was originally discovered in the hematopoietic system, where it functions as a key regulator of stem cell homeostasis, as well as neutrophil and T-cell development. Outside the blood system, Gfi1 is essential for inner-ear hair and intestinal secretory cell differentiation. To understand the regulatory hierarchies within which Gfi1 operates to control these diverse biological functions, we used a combination of comparative genomics, locus-wide chromatin immunoprecipitation assays, functional validation in cell lines, and extensive transgenic mouse assays to identify and characterize the complete ensemble of Gfi1 regulatory elements. This concerted effort identified five distinct regulatory elements spread over 100kb each driving expression in transgenic mice to a subdomain of endogenous Gfi1. Detailed characterization of an enhancer 35 kb upstream of Gfi1 demonstrated activity in the dorsal aorta region and fetal liver in transgenic mice, which was bound by key stem cell transcription factors Scl/Tal1, PU.1/Sfpi1, Runx1, Erg, Meis1, and Gata2. Taken together, our results reveal the regulatory regions responsible for Gfi1 expression and importantly establish that Gfi1 expression at the sites of hematopoietic stem cell (HSC) emergence is controlled by key HSC regulators, thus integrating Gfi1 into the wider HSC regulatory networks.