Abstract
The systemic circulation depends upon a highly organized, hierarchal blood vascular network that requires the successful specification of arterial and venous endothelial cells during development. This process is driven by a cascade of signaling events (including Hedgehog, vascular endothelial growth factor (VEGF), Notch, connexin (Cx), transforming growth factor-beta (TGF- β), and COUP transcription factor 2 (COUP-TFII)) to influence endothelial cell cycle status and expression of arterial or venous genes and is further regulated by hemodynamic flow. Failure of endothelial cells to properly undergo arteriovenous specification may contribute to vascular malformation and dysfunction, such as in hereditary hemorrhagic telangiectasia (HHT) and capillary malformation-arteriovenous malformation (CM-AVM) where abnormal vessel structures, such as large shunts lacking clear arteriovenous identity and function, form and compromise peripheral blood flow. This review provides an overview of recent findings in the field of arteriovenous specification and highlights key regulators of this process.
Highlights
Systemic blood circulation depends upon a highly organized vessel network to efficiently deliver nutrient-rich blood to, and remove waste from, peripheral tissues
Endothelial-specific mutation of Drosha in mice produces leaky, dilated microvessels and aberrant arteriovenous connections, and missense point mutations in the Drosha gene are more prevalent among patients with hemorrhagic telangiectasia (HHT) compared with healthy populations, suggesting that miRNA processing defects may contribute to the pathogenesis of this disease or modulate its severity or do both[86]
Failure of the vasculature to properly undergo arteriovenous specification may contribute to the malformation or dysfunction of blood vessels, such as occurs in patients with HHT, who exhibit aberrant vessel structures that compromise quality of life and that can even be fatal
Summary
Systemic blood circulation depends upon a highly organized vessel network to efficiently deliver nutrient-rich blood to, and remove waste from, peripheral tissues. Expression of ephrinB2, enriched in some arterial endothelial cells, and the receptor EphB4, enriched in some venous cells, is observed in the primitive vasculature prior to the onset of blood flow[11] Despite these findings, the early morphogen or morphogens that first induce formation of the initial vascular plexus and support arteriovenous specification therein remain unclear. Endothelial-specific mutation of Drosha in mice produces leaky, dilated microvessels and aberrant arteriovenous connections (but lack clear AVMs), and missense point mutations in the Drosha gene are more prevalent among patients with HHT compared with healthy populations, suggesting that miRNA processing defects may contribute to the pathogenesis of this disease or modulate its severity or do both[86] Taken together, these studies suggest that miRNAs likely play a broad role in endothelial cell specification and vascular remodeling. More work is needed to identify critical miRNA regulators of these processes and to fully elucidate their molecular roles
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