Vasostatin-2 associates with coronary collateral vessel formation in diabetic patients and promotes angiogenesis via angiotensin-converting enzyme 2

Xiao Lu Bao; Yang Dai; Lin Lu; Xiao Qun Wang; Feng Hua Ding; Wei Feng Shen; Ying Shen; Raffaele De Caterina

doi:10.1093/eurheartj/ehad082

Vasostatin-2 associates with coronary collateral vessel formation in diabetic patients and promotes angiogenesis via angiotensin-converting enzyme 2

Eur Heart J. 2023 May 14;44(19):1732-1744. doi: 10.1093/eurheartj/ehad082.

Authors

Xiao Lu Bao^{1

2}, Yang Dai², Lin Lu^{1

2}, Xiao Qun Wang¹, Feng Hua Ding¹, Wei Feng Shen^{1

2}, Ying Shen^{1

2}, Raffaele De Caterina^{3

4}

Affiliations

¹ Department of Cardiovascular Medicine, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, People's Republic of China.
² Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, 197 Rui Jin Road II, Shanghai 200025, People's Republic of China.
³ Chair of Cardiology and University Cardiology Division, Pisa University Hospital, Via Paradisa, 2, Pisa 56124, Italy.
⁴ Fondazione VillaSerena per la Ricerca-Città Sant'Angelo-Pescara, Italy.

PMID: 36861348
DOI: 10.1093/eurheartj/ehad082

Abstract

Aims: Members of the chromogranin family play a role in angiogenesis. One such biologically active peptide, generated through the processing of chromogranin A, is vasostatin-2. This study aimed at assessing the association of serum vasostatin-2 levels with coronary collateral vessels (CCV) in diabetic patients with chronic total occlusions (CTO) and the effects of vasostatin-2 on angiogenesis in diabetic mice with hindlimb or myocardial ischemia.

Methods and results: Serum levels of vasostatin-2 in 452 diabetic CTO patients were evaluated. The status of CCV was categorized according to the Rentrop score. Vasostatin-2 recombinant protein or phosphate-buffered saline were then injected intraperitoneally in diabetic mouse models of hindlimb or myocardial ischemia, followed by laser Doppler imaging and molecular biology examinations. The effects of vasostatin-2 were also ascertained in endothelial cells and macrophages, with mechanisms clarified using ribonucleic acid (RNA) sequencing. Serum levels of vasostatin-2 were significantly different and progressively higher across Rentrop score 0, 1, 2, and 3 groups (P < .001), with significantly lower levels in patients with poor CCV (Rentrop score 0 and 1) than in those with good CCV (Rentrop score 2 and 3) (P < .05). Vasostatin-2 significantly promoted angiogenesis in diabetic mice with hindlimb or myocardial ischemia. RNA-seq analyzes verified an angiotensin-converting enzyme 2 (ACE2)-mediated vasostatin-2-induction of angiogenesis in ischemic tissues.

Conclusion: Lower serum levels of vasostatin-2 are associated with poor CCV in diabetic CTO patients compared with patients with good CCV. Vasostatin-2 significantly promotes angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Such effects are mediated by ACE2.

Keywords: Angiogenesis; Angiotensin-converting enzyme 2; Coronary collateral vessels; Vasostatin-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin-Converting Enzyme 2 / metabolism
Animals
Chromogranin A / metabolism
Collateral Circulation
Coronary Artery Disease* / metabolism
Diabetes Mellitus, Experimental* / metabolism
Endothelial Cells / metabolism
Mice
Myocardial Ischemia*

Substances

vasostatin II
Chromogranin A
Angiotensin-Converting Enzyme 2