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Current dogma dictates that, during adulthood, endothelial cells (ECs) are locked in an immutable stable homeostatic state. By contrast, herein we show that maintenance of EC fate and function are linked and active processes, which depend on the constitutive cooperativity of only two ETS transcription factors (TFs), ERG and Fli1. Although deletion of either ERG or Fli1 manifests subtle vascular dysfunction, their combined genetic deletion in adult ECs results in acute vasculopathy and multi-organ failure, due to loss of EC fate and integrity, hyperinflammation and spontaneous thrombosis, leading to death. ERG and Fli1 co-deficiency causes rapid transcriptional silencing of pan and organotypic vascular core genes, with dysregulation of inflammation and coagulation pathways. Vascular hyperinflammation leads to impaired hematopoiesis with myeloid skewing. Accordingly, enforced ERG and FLI1 expression in adult human mesenchymal stromal cells activates vascular programs and functionality, enabling in vivo engraftment of a perfusable vascular network. Genome-wide association study analysis identified vascular diseases that are associated with FLI1/ERG mutations. Constitutive expression of ERG and Fli1 upholds EC fate, physiological function and resilience in adult vasculature, whereas their functional loss can contribute to systemic human diseases.

This paper represents a milestone in the UNB effort to formulate an accurate and self-consistent theory for regional geoid determination. To get the geoid to a sub-centimetre accuracy, we had to formulate the theory in a spherical rather than linear approximation, advance the modelling of the effect of topographic mass density, formulate the solid spherical Bouguer anomaly, develop the probabilistic downward continuation approach, incorporate improved satellite determined global gravitational models and introduce a whole host of smaller improvements. Having adopted Auvergne, an area in France as our testing ground, where the mean standard deviation of observed gravity values is 0.5 mGal, according to the Institute Geographique Nationale (Duquenne in Proceedings of the 1st international symposium of the international gravity field service “gravity field of the earth”, International gravity field service meeting, Istanbul, Turkey, 2006), we obtained the standard deviation of the gravity anomalies continued downward to the geoid, as estimated by minimizing the L2 norm of their residuals, to be in average 3 times larger than those on the surface with large spikes underneath the highest topographic points. The standard deviations of resulting geoidal heights range from a few millimetres to just over 6 cm for the highest topographic points in the Alpine region (just short of 2000 m). The mean standard deviations of the geoidal heights for the whole region are only 0.6 cm, which should be considered quite reasonable even if one acknowledges that the area of Auvergne is mostly flat. As one should expect, the main contributing factors to these uncertainties are the Poisson probabilistic downward continuation process, with the maximum standard deviation just short of 6 cm (the average value of 2.5 mm) and the topographic density uncertainties, with the maximum value of 5.6 cm (the average value of 3.0 mm). The comparison of our geoidal heights with the testing geoidal heights, obtained for a set of 75 control points (regularly spaced throughout the region), shows the mean shift of 13 cm which is believed to reflect the displacement of the French vertical datum from the geoid due to sea surface topography. The mean root square error of the misfit is 3.3 cm. This misfit, when we consider the estimated accuracy of our geoid, indicates that the mean standard deviation of the “test geoid” is about 3 cm, which makes it about 5 times less accurate than the Stokes–Helmert computed geoid.

The downward continuation (DWC) of the gravity anomalies from the Earth’s surface to the geoid is still probably the most problematic step in the precise geoid determination. It is this step that motivates the quasi-geoid users to opt for Molodenskij’s rather than Stokes’s theory. The reason for this is that the DWC is perceived as suffering from two major flaws: first, a physically meaningful DWC technique requires the knowledge of the irregular topographical density; second, the Poisson DWC, which is the only physically meaningful technique we know, presents itself mathematically in the form of Fredholm integral equation of the 1st kind. As Fredholm integral equations are often numerically ill-conditioned, this makes some people believe that the DWC problem is physically ill-posed. According to a revered French mathematician Hadamard, the DWC problem is physically well-posed and as such gives always a finite and unique solution. The necessity of knowing the topographical density is, of course, a real problem but one that is being solved with an ever increasing accuracy; so sooner or later it will allow us to determine the geoid with the centimetre accuracy.