EDITORIAL COMMENT
Milieu IntérieurThe Search for Myocardial Arteriogenic Signals*
Ronald W. Millard, PhD ,* and
Yigang Wang, MD, PhD
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
* Reprint requests and correspondence: Dr. Ronald W. Millard, 231 Albert Sabin Way, P.O. Box 670575, Cincinnati, Ohio 45267-0575 (Email: ron.millard{at}uc.edu).
Key Words: arteriogenesis • collateral circulation • growth substances • hemodynamics • molecular biology
Claude Bernard, the father of modern physiology, applied the scientific method to medicine and described the importance of context for physiological system functions. Bernard coined the term "milieu intérieur" (1). Today we recognize this physiological context and the intrinsic adaptive responses to maintain stable biological systems in responseto myriad physiological and pathological challenges as "homeostasis."
An expert panel consensus report on arteriogenesis (2), acknowledging Bernardian principles, concluded that: 1) arteriogenesis is the preferred type of neovascularization for purposes of restoring myocardial perfusion; 2) combination growth factor therapy or use of "master switch" genes may be optimal for clinically beneficial therapeutic angiogenesis; 3) pre-clinical and clinical studies should be preceded by tissue distribution studies to define the myocardial uptake and retention or expression of growth factor(s); and 4) protein therapy is closer to practical use than is gene therapy.
Coronary artery syndromes present homeostatic challenges. Coronary arteriogenesis is considered to be temporally shaped by endogenous intramyocardial signaling molecules. For the coronary circulation to keep pace with pathological processes (e.g., plaque formation, vasospastic behavior, adrenergic vasoconstriction) within the native coronary arteries that eventually limit coronary flow and flow reserve under times of increased cardiac demand (i.e., exercise), new coronary arterial vessel growth must match closely the loss of native coronary artery capacity and flow reserve. Failure to articulate the requisite "supply side" remodeling will result in myocardial ischemic injury and cell death.
The details of the myocardial "milieu interieur" that generates the expression of molecular signals for arteriogenesis in response to progressive coronary artery stenosis are incompletely understood. Heil et al. (3) distinguished between 2 important processes of coronary vascular growth: 1) arteriogenesis is growth of pre-existing arterio-arterial anastomoses induced by physical forces, most importantly shear stress; whereas 2) angiogenesis is induced by hypoxia and results in new capillary growth. The potential for adaptive coronary collateral growth has been appreciated for many years. Progressive coronary artery stenosis in the porcine model amply illustrates the intrinsic capacity for coronary artery collateral artery growth sufficient to support viable myocardium (4). Native and adaptive coronary circulation in humans and myriad other animals are documented by Schaper (5) and Cohen (6).
With regard to coronary arteriogenesis, endothelial cells appear to orchestrate the response to ischemia (7) by sensing changes in fluid shear stress translated by bio-signals into an integrated response. Integrins (8), tyrosine receptor kinases (9), G-protein coupled receptors (10), and ion channels (11) have each been proposed as endothelial cell membrane shear stress sensors. Signal cascades initiated by fluid shear stress changes activate endothelial cells. Adhesion molecule (intracellular adhesion molecule-1) and vascular cell adhesion molecule-1 expression are up-regulated (12). Several chemokines—tumor necrosis factor-alpha (13), granulocyte-macrophage colony-stimulating factors (14), and granulocyte colony-stimulating factor (15)—are increased, and nitric oxide is released (16). These molecules establish a new "milieu intérieur" for coronary collateral growth.
In this issue of the Journal, Schirmer et al. (17) identify new bio-molecules correlated to human coronary collateral development. Their study implicates the chemokine (C-C motif) ligand 11 (eotaxin-1) and macrophage migration inhibitory factor in coronary arteriogenesis. These molecules, emanating from the "milieu intérieur" of human heart tissue are postulated to participate in the complex interplay of signals remodeling myocardium and coronary collaterals.
An important question arising from the outcomes and speculations of this study is: Can arteriogenic or angiogenic factor(s) improve cardiac pump function after scar is formed by promoting myocardial neovascularization? This study provides no information on this. To date, clinical trials testing single arteriogenic bio-molecules have demonstrated insufficient efficacy or unacceptable side effects (18–20). Gene transfer from implanted cells has been shown to induce myocardial angiogenesis (21) as has combination proteins—fibroblast growth factor-2 with platelet-derived growth factor BB (22). Enhancement of the intrinsic myocardial stromal cell-derived factor can recruit pluripotent mesenchymal stem cells to generate new cardiac myocytes and new blood vessels (23).
Clinical trials (24) are currently exploring safety and efficacy of: 1) bone marrow stem cells; 2) endothelial progenitor cells; 3) bicistronic vascular endothelial growth factor-A 165/basic fibroblast growth factor plasmid; 4) gene transfer of vascular endothelial growth factor combined with oral L-arginine supplementation; and 5) adenovirus serotype-5 mediated fibroblast growth factor-4 gene transfer, among others.
Clinical studies such as that reported here by Schirmer et al. (17), while presenting some surmountable limitations (coronary sampling rate and method, and fixed venous pressure in coronary collateral flow index calculations), have identified new molecular signals possibly involved in coronary arteriogenesis. Results from such studies may provide important clues for future coronary arteriogenic therapies. Experimental studies in models that reflect human coronary collateral biology will allow in situ tissue characterization of relevant signaling molecules. Meanwhile, Schirmer et al. (25) continue expanding our understanding of arteriogenesis and its molecular signals.
Taken together, the search for myocardial signal molecules that support arteriogenesis remains an active area of investigation engaging basic research models, translational efforts, and clinical trials. It is likely that time will reinforce the Bernardian view that no one molecular entity or technological approach may be the "master switch" controlling the molecular signaling cascade establishing a new "milieu intérieur" for arteriogenesis.
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Footnotes
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This work was partially supported by National Institutes of Health award HL-089824.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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Neoangiogenesis by local gene therapy: a new therapeutic concept in the treatment of coronary disease [in German] Z Kardiol 2000;89(Suppl 7):23-30.[Medline] 20. Kastrup J, Jorgensen E, Ruck A, et al. Euroinject One Group Direct intramyocardial plasmid vascular endothelial growth factors-A165 gene therapy in patients with stable severe angina pectoris. A randomized double-blind placebo-controlled study: the Euorinject One trial J Am Coll Cardiol 2005;45:982-988.[Abstract/Free Full Text] 21. Yau TM, Fung K, Weisel RD, Fujii T, Mickle DAG, Li R-K. Enhanced myocardial angiogenesis by gene transfer with transplanted cells Circulation 2001;104:I218-I222.[Web of Science][Medline] 22. Lu H, Xu X, Zhang M, et al. Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs Proc Natl Acad Sci U S A 2007;104:12140-12145.[Abstract/Free Full Text] 23. Zhao T, Zhang D, Millard RW, Ashraf MN, Wang Y. Stem cell homing and angiomyogenesis in transplanted hearts are enhanced by combined intramyocardial SDF-1 delivery and endogenous cytokine signaling Am J Physiol Heart Circ Physiol 2009;296:H976-H986.[Abstract/Free Full Text] 24. ClinicalTrials.gov, a service of the U.S. National Institutes of Health. Available at: http://clinicaltrials.gov. Accessed January 19, 2009. 25. Schirmer SH, van Nooijen FC, Piek JJ, van Royen N. Stimulation of collateral artery growth: travelling further down the road to clinical application Heart 2009;95:191-197.[Abstract/Free Full Text]
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