Arterial Venous Differentiation for Vascular Bioengineering

Abstract

The development processes of arteries and veins are fundamentally different, leading to distinct differences in anatomy, structure, and function as well as molecular profiles. Understanding the complex interaction between genetic and epigenetic pathways, as well as extracellular and biomechanical signals that orchestrate arterial venous differentiation, is not only critical for the understanding of vascular diseases of arteries and veins but also valuable for vascular tissue engineering strategies. Recent research has suggested that certain transcriptional factors not only control arterial venous differentiation during development but also play a critical role in adult vessel function and disease processes. This review summarizes the signaling pathways and critical transcription factors that are important for arterial versus venous specification. We focus on those signals that have a direct relation to the structure and function of arteries and veins, and have implications for vascular disease processes and tissue engineering applications.

Keywords: arterial venous endothelial cells; stem cell differentiation; vascular bioengineering; vascular development.

Figure 1

Formation of arteries and veins. During early development, vascular progenitors, also known as angioblasts, that are differentiated from mesoderm start to acquire either arterial or venous fate, and they assemble into a primary network called the vascular plexus. The vascular plexus subsequently undergoes extensive remodeling through EphrinB2/EphB4-mediated cell repulsion into arterial and venous territories. Meanwhile, nerve-derived signals align the blood vessels and cause arterial differentiation. When the heart starts to beat, the arterial blood vessels are exposed to higher blood pressure and flow, which further drive arterial differentiation and mature phenotype maintenance. Abbreviations: COUP-TF11, chicken ovalbumin upstream promoter transcription factor 2; Cx40: connexin 40; Dll4, delta-like ligand 4; Nrp2, Neuropilin-2; Sox17, sex-determining region Y box 17; VEGF, vascular endothelial growth factor.

Figure 2

The key transcriptional programs and signaling pathways in determining arterial and venous identities. Abbreviations: BRG1, Brahma-related gene 1; COUP-TFII, chicken ovalbumin upstream promoter transcription factor 2; Cx40, connexin 40; Dll4, delta-like ligand 4; MAPK, mitogen-activated protein kinase; NICD, Notch intracellular domain; Nrp1, Neuropilin-1; Nrp2, Neuropilin-2; PI3K, phosphatidylinositol 3-kinase; RBPJ, recombining binding protein suppressor of hairless; Sox17, sex-determining region Y box 17; VEGF, vascular endothelial growth factor; VEGFR2, vascular endothelial growth factor receptor 2.

Figure 3

Arterial and venous endothelial cells have different gene expression profiles related to the functional status of the endothelium. Endothelial messenger RNA was isolated from mouse aorta and vena cava and subjected to transcriptional profiling analysis. Modified from Reference .

Figure 4

Selected highly differentially expressed genes in aorta versus vena cava endothelial cells. Modified from Reference .