Circulation is established in a stepwise pattern in the mammalian embryo

Abstract

To better understand the relationship between the embryonic hematopoietic and vascular systems, we investigated the establishment of circulation in mouse embryos by examining the redistribution of yolk sac-derived primitive erythroblasts and definitive hematopoietic progenitors. Our studies revealed that small numbers of erythroblasts first enter the embryo proper at 4 to 8 somite pairs (sp) (embryonic day 8.25 [E8.25]), concomitant with the proposed onset of cardiac function. Hours later (E8.5), most red cells remained in the yolk sac. Although the number of red cells expanded rapidly in the embryo proper, a steady state of approximately 40% red cells was not reached until 26 to 30 sp (E10). Additionally, erythroblasts were unevenly distributed within the embryo's vasculature before 35 sp. These data suggest that fully functional circulation is established after E10. This timing correlated with vascular remodeling, suggesting that vessel arborization, smooth muscle recruitment, or both are required. We also examined the distribution of committed hematopoietic progenitors during early embryogenesis. Before E8.0, all progenitors were found in the yolk sac. When normalized to circulating erythroblasts, there was a significant enrichment (20-to 5-fold) of progenitors in the yolk sac compared with the embryo proper from E9.5 to E10.5. These results indicated that the yolk sac vascular network remains a site of progenitor production and preferential adhesion even as the fetal liver becomes a hematopoietic organ. We conclude that a functional vascular system develops gradually and that specialized vascular-hematopoietic environments exist after circulation becomes fully established. IntroductionA functional circulatory system is an early requirement for survival and growth of the mammalian embryo and is the first organ system to develop in the embryo. 1 The circulatory system is composed of vascular, hematopoietic, and cardiac components, each formed from discrete regions of mesoderm. The first endothelial cells and blood cells are generated in yolk sac blood islands beginning at embryonic day 7 (E7.0) in the mouse. By E8.0, thousands of nucleated primitive red blood cells have formed within a vascular plexus in the yolk sac. [2][3][4] Concurrently, the aorta and the peristaltic beating heart tube form in the embryo proper. In the next 36 hours, there is a remarkable increase in complexity of vascular and hematopoietic systems. The vascular plexus remodels and expands into an arborized network of specialized arteries and veins. Primitive erythroblasts from the yolk sac continue to divide and mature, and a second wave of hematopoiesis creating definitive (adultlike) progenitors originates in the yolk sac. 5,6 Thus, the early vascular system is the hematopoietic environment for primitive and definitive lineages until the specialized stromal microenvironment of the fetal liver (beginning E10), and later the adult bone marrow, is available. However, the nature of any specific interactions between early embryonic hematopo...

High‐frequency ultrasonographic imaging of avian cardiovascular development

“…Our observations of only a few isolated circulating cells at the early stages are consistent with the low hematocrits documented in the earliest stages of the circulation by the studies of Rychter et al in chicken embryos (Rychter et al, 1955) and more recently also in the mammalian circulation (McGrath et al, 2003). At later stages, echogenicity of blood increases significantly, because of nucleation and dimensions of the red blood cells.…”

“…Tracking of these objects frame-byframe provided the opportunity to estimate particle velocity in the dorsal aortae. The average particle movement per heart beat was 0.16 Ϯ 0.05 mm (mean Ϯ SD, n ϭ 8), and the average velocity 0.64 Ϯ 0.15 mm/s (n ϭ 6), which is close to values reported for vessels of similar dimensions in the yolk sac of older mouse embryos (McGrath et al, 2003). From these values, we determined that each stroke moved a volume approximately 2.5 ϫ 10 -3 mm 3 , within the range of previously reported filling volumes of 4.2 ϫ 10 -3 mm 3 for a stage-12 chick embryonic ventricle and stroke volumes of 0.01 mm 3 .…”

Restricted inactivation of serum response factor to the cardiovascular system

“…Functional circulation reaches a steady state at e10.0-e10.5 days of gestation in the mouse (26). This embryonic period is pivotal for normal cardiovascular development, as evidenced by the ever-increasing number of lethal phenotypes that are linked to the heart and blood vessels at this time point (http:͞͞research.bmn.com͞mkmd).…”

Role of serum response factor in the pathogenesis of disease

“…50 Expression of SRF is already evident in vascular SMCs at Be10.5 of development, 34 a time coinciding with the expression of several SMC contractile genes [51][52][53][54] and the establishment of a functional circulatory system. 55 The only reported knockout of SRF in vascular SMCs used the Sm22a promoter, 32 which is active in embryonic SMCs, the developing heart, and somites. 56 The heart phenotype is very similar to that reported by others (Table 1).…”