Vascular endothelial cell specification in health and disease

Abstract

There are two vascular networks in mammals that coordinately function as the main supply and drainage systems of the body. The blood vasculature carries oxygen, nutrients, circulating cells, and soluble factors to and from every tissue. The lymphatic vasculature maintains interstitial fluid homeostasis, transports hematopoietic cells for immune surveillance, and absorbs fat from the gastrointestinal tract. These vascular systems consist of highly organized networks of specialized vessels including arteries, veins, capillaries, and lymphatic vessels that exhibit different structures and cellular composition enabling distinct functions. All vessels are composed of an inner layer of endothelial cells that are in direct contact with the circulating fluid; therefore, they are the first responders to circulating factors. However, endothelial cells are not homogenous; rather, they are a heterogenous population of specialized cells perfectly designed for the physiological demands of the vessel they constitute. This review provides an overview of the current knowledge of the specification of arterial, venous, capillary, and lymphatic endothelial cell identities during vascular development. We also discuss how the dysregulation of these processes can lead to vascular malformations, and therapeutic approaches that have been developed for their treatment.

Keywords: Arterial-venous malformations; Blood vessel development; Endothelial cell specification; Lymphatic malformations; Lymphatic vessel development.

Fig. 1

Blood EC Specification in Health and Disease. (Black) Primordial endothelial cells (ECs) are specified from mesoderm-derived cells and form primitive vascular plexi. Expansion and maturation of these plexi through vasculogenesis and angiogenesis forms the adult vascular network. Several developmental pathways play a significant role in initial EC specification and later in determination of arterial-venous fates. (Red) Changes to key signaling components in these specification pathways are associated with the development of human arteriovenous malformations, including Cutaneo-mucosal venous malformations (VMCM); capillary malformation with arteriovenous malformations (CM-AVM); cerebral cavernous malformations (CCM); and hereditary hemorrhagic telangiectasia (HHT)

Fig. 2

Lymphatic EC Specification and Lymphatic Valve Development. (Black) Lymphatic ECs (LECs) are specified from venous and non-venous progenitor cells. LECs form the embryonic lymphatic circulation through lymphangiogenesis and lymphvasculogenesis. Collecting lymphatic vessels have intraluminal valves which are formed from LECs with a high expression of PROX1 (PROX1^high) and involves an intricate network of signaling pathways and transcription factors. (Red) Pathways disrupted in human lymphatic development that contribute to lymphatic malformations and lymphedema