Heterogeneity in endothelial cells and widespread venous arterialization during early vascular development in mammals

Yu Hou,Yun Gao,Xiaowei Ning,Qian Xin,Ji Dong,Shuaili Li,Zongcheng Li,Bing Liu,Fuchou Tang,Xiaoying Fan,Xianlong Li,Siyuan Hou,Yuqiong Hu,Bin Zhou,Zhilin Chang,Yanli Ni,Xiaochen Ding,Baihan Wang,Yang Zeng,Lu Wen,Yunqiao Li,Yu Lan

doi:10.1038/s41422-022-00615-z

Abstract

Arteriogenesis rather than unspecialized capillary expansion is critical for restoring effective circulation to compromised tissues in patients. Deciphering the origin and specification of arterial endothelial cells during embryonic development will shed light on the understanding of adult arteriogenesis. However, during early embryonic angiogenesis, the process of endothelial diversification and molecular events underlying arteriovenous fate settling remain largely unresolved in mammals. Here, we constructed the single-cell transcriptomic landscape of vascular endothelial cells (VECs) during the time window for the occurrence of key vasculogenic and angiogenic events in both mouse and human embryos. We uncovered two distinct arterial VEC types, the major artery VECs and arterial plexus VECs, and unexpectedly divergent arteriovenous characteristics among VECs that are located in morphologically undistinguishable vascular plexus intra-embryonically. Using computational prediction and further lineage tracing of venous-featured VECs with a newly developed Nr2f2CrexER mouse model and a dual recombinase-mediated intersectional genetic approach, we revealed early and widespread arterialization from the capillaries with considerable venous characteristics. Altogether, our findings provide unprecedented and comprehensive details of endothelial heterogeneity and lineage relationships at early angiogenesis stages, and establish a new model regarding the arteriogenesis behaviors of early intra-embryonic vasculatures.

Highlights

During mammalian embryogenesis, the cardiovascular system is the first functional organ system to form
The arterial plexus Vascular endothelial cells (VECs) identified here presumably correspond to the pre-artery cells that are defined in the coronary capillary vessels, as both of them are morphologically indistinguishable from their neighboring VECs in the vascular plexus but display apparent arterial characteristics
The venous-to-arterial fate conversion is known to occur in later stages of organogenesis and be confined to specific organs; e.g., the coronary arteries are initially formed from venous VECs of the sinus venosus.[10,11]

Summary

INTRODUCTION

The cardiovascular system is the first functional organ system to form. EP0 mainly contained display different properties that correspond to distinct vascular beds[13,14] and present an arterial-capillary-venous zonation and seamless continuum of transcriptional states.[13,15] scRNA-seq has cells from E8.0 embryos, indicative of its features of primordial VECs (Fig. 1b–e). These earliest VECs may originate independently, their molecular characteristics were similar.

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS