Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are uniquely required to balance the formation of new blood vessels with the maintenance and remodelling of existing ones, during development and in adult tissues. Recent advances have greatly expanded our understanding of the tight and multi-level regulation of VEGFR2 signalling, which is the primary focus of this Review. Important insights have been gained into the regulatory roles of VEGFR-interacting proteins (such as neuropilins, proteoglycans, integrins and protein tyrosine phosphatases); the dynamics of VEGFR2 endocytosis, trafficking and signalling; and the crosstalk between VEGF-induced signalling and other endothelial signalling cascades. A clear understanding of this multifaceted signalling web is key to successful therapeutic suppression or stimulation of vascular growth.

The effects of hemodynamic forces upon vascular endothelial cell turnover were studied by exposing contact-inhibited confluent cell monolayers to shear stresses of varying amplitude in either laminar or turbulent flow. Laminar shear stresses (range, 8-15 dynes/cm2; 24 hr) induced cell alignment in the direction of flow without initiating the cell cycle. In contrast, turbulent shear stresses as low as 1.5 dynes/cm2 for as short a period as 3 hr stimulated substantial endothelial DNA synthesis in the absence of cell alignment, discernible cell retraction, or cell loss. The results of these in vitro experiments suggest that in atherosclerotic lesion-prone regions of the vascular system, unsteady blood flow characteristics, rather than the magnitude ofwall shear stressperse, may be the major determinant of hemodynamically induced endothelial cell turnover.Hemodynamic forces have been implicated in the initiation, localization, and development of atherosclerotic vascular disease (1, 2). Little is known, however, about the effects of such forces upon the endothelial cell lining of blood vessels, the integrity of which is essential for normal vascular function. In certain areas ofthe aorta and its main branches, blood flow characteristics are both variable and complex. In locations such as the descending thoracic aorta and distal carotid arteries, pulsatile laminar flow is prevalent (3), whereas in other regions, such as coronary arteries and the carotid bifurcation, secondary flows, vortices, and intermittently changing flow directions are encountered (4). The distribution of atherosclerotic lesions in susceptible species, including humans, is closely correlated with the location of disturbed flow in the major vessels (5). Time-dependent flow separation and unsteady secondary flow typically occur in localized regions that are usually well defined and of limited size. Furthermore, turbulence will occur in the largest arteries under conditions of increased flow velocity and cardiac output (4). Thus, shear stresses, which are the direct tractive forces acting on the endothelial cell surface as a result of blood flow, are highly variable in magnitude, frequency, and direction in such regions.Autoradiographic studies in vivo have demonstrated increased endothelial DNA synthesis in localized areas of the aorta and its major branches, suggesting that locally increased endothelial cell turnover, perhaps as a result of injury, may occur near branches and bifurcations (6, 7). Increased cell turnover need not imply denudation of the endothelium and indeed during the initiation and early development of atherosclerotic lesions the endothelium remains a confluent monolayer of cells (8).The role of fluid shear stress in promoting endothelial cell injury and/or turnover is uncertain: both high and low shear stresses have been implicated. High shear stress has been linked to alignment of endothelial cells (9), cell loss (10), increased arterial permeability (11), and enhanced endothelial biosynthetic capabilities (12). Ath...

SUMMARY Activin receptor-like kinase 1 (ALK1) is an endothelial-specific member of the TGF-β/BMP receptor family that is inactivated in patients with hereditary hemorrhagic telangiectasia (HHT). How ALK1 signaling regulates angiogenesis remains incompletely understood. Here we show that ALK1 inhibits angiogenesis by cooperating with the Notch pathway. Blocking Alk1 signaling during postnatal development in mice leads to retinal hypervascularization and the appearance of arteriovenous malformations (AVMs). Combined blockade of Alk1 and Notch signaling further exacerbates hypervascularization, whereas activation of Alk1 by its high-affinity ligand BMP9 rescues hypersprouting induced by Notch inhibition. Mechanistically, ALK1-dependent SMAD signaling synergizes with activated Notch in stalk cells to induce expression of the Notch targets HEY1 and HEY2, thereby repressing VEGF signaling, tip cell formation, and endothelial sprouting. Taken together, these results uncover a direct link between ALK1 and Notch signaling during vascular morpho-genesis that may be relevant to the pathogenesis of HHT vascular lesions.

Genomic imprinting, by which maternal and paternal alleles of some genes have different levels of activity, has profound effects on growth and development of the mammalian fetus. The action of imprinted genes after birth, in particular while the infant is dependent on maternal provision of nutrients, is far less well understood. We disrupted a paternally expressed transcript at the Gnas locus, Gnasxl, which encodes the unusual Gs alpha isoform XL alpha s. Mice with mutations in Gnasxl have poor postnatal growth and survival and a spectrum of phenotypic effects that indicate that XL alpha s controls a number of key postnatal physiological adaptations, including suckling, blood glucose and energy homeostasis. Increased cAMP levels in brown adipose tissue of Gnasxl mutants and phenotypic comparison with Gnas mutants suggest that XL alpha s can antagonize Gs alpha-dependent signaling pathways. The opposing effects of maternally and paternally expressed products of the Gnas locus provide tangible molecular support for the parental-conflict hypothesis of imprinting.