Letter to the Editor on: “Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells.”

Dear Editor

Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells

After reading the fascinating review article entitled “Effects of Exercise Training on the Paracrine Function of Circulating Angiogenic Cells” [1] as well as the other articles by the same authors [2] [3] we wonder why endothelial progenitor cells (EPCs) have been replaced with circulating angiogenic cells (CACs). Within the bloodstream there are many cells, particles, proteins, cytokines, non-coding mRNA etc. The stimulus of muscular exercise releases numerous stem cells, progenitor cells, angiogenic cells and more than 9000 proteins within the circulation [4] and the challenge is to identify their distinct and proper function for each one, if possible.

Both EPCs and CACs which are defined by similar surface markers possess angiogenic capabilities, regenerate damaged endothelium, and perform paracrine function. EPCs seem to go a step forward; as progenitor cells connect the bone marrow with the functional endothelium, supply a sufficient number of endothelial cells and have the capacity to form de novo, in vivo blood vessels. On the other hand, CACs represent “in vitro” myeloid cells and promote angiogenesis only through a paracrine mechanism. To better understand, CACs are behind in including stem cells, progenitor cells, monocytes macrophages, mesenchymal stem cells and T-cells [1] in the process of angiogenesis.

We agree with the authors [1] that the above cells may play a distinct role in vascular repair but may be secondary or need to be investigated further. Who knows the degree of vascularization and the potent intrinsic angiogenic capacity of each cell unit? Which paracrine angiogenic action is more effective? Can the answer be CACs since they include everything? Do we understand the contribution of each cell unit under the name of CACs? CACs present both strengths and weaknesses in collecting various circulating cells under the angiogenic term. EPCs possess angiogenic ability and all the distinct characteristics of CACs. In addition, although 50% of the cited publications of the review article belong to the EPC studies (see the literature in [Table 1]), they have been renamed and presented as CACs. This is correct according to the definition of CACs. In contrast, CACs can be determined as EPCs only when similar methods of identification and surface markers are used.

Table 1 Number of publications entitled EPC or CAC nomenclature without or with exercise (Cochrane Database).

	EPCs	CACs	EPCs & exerc	CACs & exerc
Total ~25 yrs (No)	812	136	115	26
Last 5 yrs (No)	295	49	48	8
Last 3 yrs (No)	160	23	28	3

CACs: circulating angiogenic cells; EPCs: endothelial progenitor cells.

The dilemma whether one term is more proper than the other awaits to be solved. EPCs have been adopted in our publications [5] [6] and we had no objections to use CACs in our recent paper [5]. Nevertheless, our surface markers (CD34/CD45/CD133/KDR or VEGFR₂) can precisely identify the endothelium-oriented progenitor cells in CACs as well as in EPCs. The cell surface markers adopted by the authors (CD31 and CD14) [1], however, were not included in our EPC identification [5]. We do not really know if different surface markers can identify similar or different cell populations with distinct lineages and functions. In addition, the general CACs terminology accepts and includes EPCs as well as many other cells and this raises the issue of ambiguity. What is the functional diversity of the subpopulation of CACs? The EPCs (a “subpopulation” of CACs) protect endothelium, appear to be concise and specific in origin (progenitor) and function (paracrine and angiogenic), and provide clarity.

A general term of Pluripotent Circulated or Angiogenic or Endothelial Cell may offer a solution or may lead to misconception. Sufficient evidence indicates that EPCs mainly participate in the process of vascular repair which presumably originates from bone marrow-derived hematopoietic stem cells [7] as well as from non-hematopoietic non-bone marrow cell sources [8]. Nevertheless, the lack of consistent evidence concerning nomenclature and definition for clinical application, generates more confusion than comprehension [9]. Indeed, Balistreri and colleagues stated that there is “lack of standardized criteria and consensus for defining, characterizing, and Identifying EPCs with well-established surface markers, protocols, and methods” [9] The term EPC was adopted (described by CD34⁺/CD133⁺/CD45^- cells) in our laboratory. The same term was adopted (as a subpopulation of CACs) by the authors and the following question was raised: how can someone select circulating angiogenic cells (CACs), circulating endothelial cells (CECs), circulating hematopoietic progenitor cells (CHPCs), circulating endothelial progenitors cells (CEPCs) or endothelial progenitor cells (EPCs) and be sure that he uses the proper one? Reviewing the relevant literature, one can almost reach the theory of ‘putative’ [9] or nonexistent cells. We remain open to any further recommendations.

Publication History

Article published online:
03 November 2021

• References

• 1 Evans WS, Sapp RM, Kim KI. et al. Effects of exercise training on the paracrine function of circulating angiogenic cells. Int J Sports Med 2021; 42: 1047–1057
• 2 Landers-Ramos RQ, Sapp RM, Shill DD. et al. Exercise and cardiovascular progenitor cells. Compr Physiol 2019; 9: 767-797
• 3 Landers-Ramos RQ, Sapp RM, VandeWater E. et al. Investigating the extremes of the continuum of paracrine functions in CD34^-/CD31⁺CACs across diverse populations. Am J Physiol Heart Circ Physiol 2017; 312: H162-H172
• 4 Whitham M, Febbraio M. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat Rev Drug Discov 2016; 15: 719–729
• 5 Mitsiou G, Karatzanos E, Smilios I. et al. Exercise promotes endothelial progenitor cell mobilization in patients with chronic heart failure. Eur J Prev Cardiol 2020. Online ahead of print. 10.1093/eurjpc/zwaa046
• 6 Volaklis KA, Tokmakidis SP, Halle M. Acute and chronic effects of exercise on circulating endothelial progenitor cells in healthy and diseased patients. Clin Res Cardiol 2013; 102: 249-257
• 7 Chopra H, Hung MK, Kwong DL. et al. Insights into endothelial progenitor cells: origin, classification, potentials, and prospects. Stem Cells Int 2018; 2018: 9847015
• 8 Aicher A, Rentsch M, Sasaki K. et al. Nonbone marrow-derived circulating progenitor cells contribute to postnatal neovascularization following tissue ischemia. Circ Res 2007; 100: 581-589
• 9 Balistreri CR, Buffa S, Pisano C. et al. Are endothelial progenitor cells the real solution for cardiovascular diseases? Focus on controversies and perspectives. Biomed Res Int 2015; 2015: 835934