Role of Venous Endothelial Cells in Developmental and Pathologic Angiogenesis

Abstract

Background: Angiogenesis is a dynamic process that involves expansion of a pre-existing vascular network that can occur in a number of physiologic and pathologic settings. Despite its importance, the origin of the new angiogenic vasculature is poorly defined. In particular, the primary subtype of endothelial cells (capillary, venous, arterial) driving this process remains undefined. Methods: Endothelial cells were fate-mapped using genetic markers specific to arterial, capillary cells. In addition, we identified a novel venous endothelial marker gene ( Gm5127 ) used it to generate inducible venous endothelial-specific Cre and Dre driver mouse lines. Contributions of these various types of endothelial cells to angiogenesis were examined during normal postnatal development and in disease-specific setting. Results: Using a comprehensive set of endothelial subtype-specific inducible reporter mice, including tip-, arterial- and venous- endothelial reporter lines, we showed that venous endothelial cells are the primary endothelial subtype responsible for the expansion of an angiogenic vascular network. During physiologic angiogenesis, venous endothelial cells proliferate, migrating against the blood flow, and differentiating into tip, capillary and arterial endothelial cells of the new vasculature. Using intravital 2-photon imaging, we observed venous endothelial cells migrating against the blood flow to form new blood vessels. Venous endothelial cell migration also plays a key role in pathologic angiogenesis. This was observed both in formation of arterio-venous malformations in mice with inducible endothelial-specific Smad4 deletion mice and in pathologic vessel growth seen in oxygen-induced retinopathy. Conclusions: Our studies establish venous endothelial cells are primary endothelial subtype responsible for the normal expansion of vascular networks, formation of arterio-venous malformations and pathologic angiogenesis. These observations highlight the central role of the venous endothelium in normal development and disease pathogenesis.

The Role of CCL2/CCR2 Axis in Cerebral Ischemia-Reperfusion Injury and Treatment: From Animal Experiments to Clinical Trials

“…After ischemic stroke, if the formation of new blood vessels in the ischemic penumbra is promoted, blood reperfusion can be increased, which is beneficial to reducing the volume of cerebral infarction, neuronal remodeling, prolonging survival times, and functional recovery [ 111 , 112 ]. Angiogenesis is a dynamic process that is induced by the sprouting of endothelial cells (ECs) from pre-existing vessels, thus expanding the pre-existing vascular network [ 113 ]. Under a number of physiological and pathological conditions, the endothelial cells degrade the basement membrane, migrate to adjacent tissues, proliferate, and aggregate into tubular shape, thereby forming new blood vessels.…”

Flow goes forward and cells step backward: endothelial migration

“…Because endothelial cells in the capillary bed are embedded in thinner basement membranes than those in arteries and veins 36 , 37 , it has been hypothesized that capillary endothelial cells are the source of endothelial expansion. However, this idea has been challenged by recent findings that venous endothelial cells are the primary source of endothelial cells for angiogenic expansion during developmental and pathological angiogenesis 8 .…”

“…A recent study 8 reported that venous endothelial cells are the primary source of endothelial cells responsible for angiogenic expansion both during embryonic development and in disease settings. Remarkably, venous endothelial cells are the only type of endothelial subtype capable of responding to hypoxia-induced angiogenic signaling by proliferating and migrating against the blood flow to form the new vascular bed.…”

Defining specific cell states of MPTP-induced Parkinson’s disease by single-nucleus RNA sequencing

“…4i, g and SM 4). About half of the overlapped genes have been found to be related to PD in previous studies, and the rest genes are related to neuropsychiatric diseases (Zbtb20, Nav3), tissue aging (Myof), impaired memory (Atp10a), blood-brain barrier (Slco1a4/5, Cldn5, Ly6a) [44][45][46] .…”