Endocardial transcription factor HAND2 orchestrates hypoxic and TGF-β signaling to modulate coronary artery formation

Huijuan Wang; Haosheng Zhang; Leiyin Zheng; Peihan Zhang; Yuqian Wang; Sijia Ding; Wenping Liu; Yuanming Cheng; Zhongzhou Yang; Wen Luo

doi:10.1172/JCI203310

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

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¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Zhang, H. in: PubMed | Google Scholar

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Zheng, L. in: PubMed | Google Scholar

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Zhang, P. in: PubMed | Google Scholar

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

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¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Ding, S. in: PubMed | Google Scholar

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Liu, W. in: PubMed | Google Scholar

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Cheng, Y. in: PubMed | Google Scholar

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Yang, Z. in: PubMed | Google Scholar

¹Department of Vascular Surgery, Nanjing University, Nanjing, China

²Department of Hematology, Nanjing University, Nanjing, China

³State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China

Find articles by Luo, W. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI203310.
Copyright © 2026, Wang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published August 6, 2026 - Version history

The endocardium is a major source of coronary angiogenesis and arterialization, through coordinated cell fate transition and migration. However, the transcriptional regulatory network synchronizing cell fate determination and movement remains unclear. Here, we identified transcription factor HAND2 as a key candidate for coronary vascular formation. Endocardial deletion of Hand2 in mice disrupted arterial-venous networks and stunted coronary arteries, paralleling a ventricular noncompaction phenotype. Moreover, deletion of Hand2 produced excessive tip cells with defective movement. RNA-seq analysis revealed enhanced hypoxic metabolic activation but declined TGF-β/p38MAPK-dependent endothelial-to-mesenchymal transition (Endo-MT). In consistence, genetic inhibition of the core hypoxic regulators or pharmaceutical administration of TGFβ2 partially recovered the coronary arterial defects in Hand2 mutants. Furthermore, HAND2 was found directly bound to promoters of the target genes, harmonizing cell migration and cell fate transition. These findings pinpoint HAND2 as an essential regulator of the endocardial transcriptional regulatory network for coronary arterialization and provide potential therapeutic targets for coronary artery diseases.

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Endocardial transcription factor HAND2 orchestrates hypoxic and TGF-β signaling to modulate coronary artery formation

Huijuan Wang,¹ Haosheng Zhang,² Leiyin Zheng,¹ Peihan Zhang,¹ Yuqian Wang,¹ Sijia Ding,¹ Wenping Liu,¹ Yuanming Cheng,³ Zhongzhou Yang,³ and Wen Luo¹

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Endocardial transcription factor HAND2 orchestrates hypoxic and TGF-β signaling to modulate coronary artery formation

Huijuan Wang,1 Haosheng Zhang,2 Leiyin Zheng,1 Peihan Zhang,1 Yuqian Wang,1 Sijia Ding,1 Wenping Liu,1 Yuanming Cheng,3 Zhongzhou Yang,3 and Wen Luo1

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Huijuan Wang,¹ Haosheng Zhang,² Leiyin Zheng,¹ Peihan Zhang,¹ Yuqian Wang,¹ Sijia Ding,¹ Wenping Liu,¹ Yuanming Cheng,³ Zhongzhou Yang,³ and Wen Luo¹