Combinatorial protein therapy of angiogenic and arteriogenic factors remarkably improves collaterogenesis and cardiac function in pigs

Abstract

Establishment of functional and stable collaterals in the ischemic myocardium is crucial to restoring cardiac function after myocardial infarction. Here, we show that only dual delivery of a combination of angiogenic and arteriogenic factors to the ischemic myocardium could significantly reestablish stable collateral networks and improve myocardial perfusion and function. A combination of FGF-2 with PDGF-BB, two factors primarily targeting endothelial cells and vascular smooth muscle cells, remarkably promotes myocardial collateral growth and stabilizes the newly formed collateral networks, which significantly restore myocardial perfusion and function. Using various members of the PDGF family together with FGF-2 in an angiogenesis assay, we demonstrate that PDGFR-␣ is mainly involved in angiogenic synergism, whereas PDGFR-␤ mediates vessel stability signals. Our findings provide conceptual guidelines for the clinical development of proangiogenic/arteriogenic factors for the treatment of ischemic heart disease.angiogenesis ͉ growth factor ͉ ischemia ͉ myocardial infarction ͉ neovascularization A therosclerosis-induced coronary artery disease is the leading cause of morbidity and mortality in Western societies and increases at an alarming rate in developing countries (1). Usually, progressive atherosclerosis results in plaque rupture and thrombosis of major coronary arteries, leading to angina, myocardial infarction, and heart failure (2). Except for surgical interventions, an effective therapeutic method for treatment has been lacking. Although delivery of proangiogenic factors to the ischemic myocardium to stimulate collaterogenesis and to improve myocardial perfusion and function is a straightforward idea proposed for Ͼ30 years, clinical evaluation of these individual proangiogenic molecules has produced unfulfilled promises (3-5). After more than a decade of clinical practice with different single proangiogenic factors for the treatment of ischemic disorders, almost all large randomized, double-blinded, and placebo-controlled human trials have proven to be nonbeneficial (6-8).The clinical failures with this attractive approach have raised several unresolved fundamental issues regarding the basic mechanisms of cardiovascular biology. These include the underlying mechanisms of angiogenesis versus arteriogenesis, choice of proangiogenic agents, monotherapy versus combinatorial therapy, appropriate animal models for preclinical evaluation, optimal drug release systems, and time line of delivery. For improvement of perfusion of high-oxygenated blood in ischemic tissues, it is essential to reestablish functional arterial vascular networks, which should remain stable long-term. Most previous preclinical and clinical studies on the development of proangiogenic therapies for treating ischemic myocardium have been based on monotherapeutic approaches (9-20). These approaches usually lack rationales for understanding the molecular mechanisms of arteriogenesis, for defining molecular targets of the deliverable proangiogeni...

TGF-β1 signaling and Krüppel-like factor 10 regulate bone marrow–derived proangiogenic cell differentiation, function, and neovascularization

“…Several studies have shown that PDGF-AB and PDGF-AA are indispensable for angiogenic events and are necessary for stabilizing newly formed blood vessels. [33][34][35] These chemokines may be important in the recruitment of other PACs or leukocytes, which in turn contribute to development and progression of angiogenesis 36 ; for example, MCP-1 can recruit PACs to a wound site to accelerate re-endothelialization. 37 Finally, although CMP-and GMP-derived PACs were able to elaborate higher levels of VEGF compared with MEP-or HSC-derived PACs, 10 we were surprised to find a striking absence of a decrease in the elaboration of VEGF in KLF10 Ϫ/Ϫ CMP-and GMP-derived PACs compared with WT PACs (data not shown).…”

Prostaglandin E 2 Primes the Angiogenic Switch via a Synergic Interaction With the Fibroblast Growth Factor-2 Pathway

“…[31][32][33] In the light of our findings, we propose a model for the angiogenic switch based on the autocrine/paracrine FGF-2/FGFR1 activation by PGE 2 and FGF-2 synergistic interaction. FGFR1 acts as the master switch, because its activation by FGF-2 initiates an autocrine cycle of FGF-2 synthesis and FGFR1 activation.…”

Formation of Stable Vascular Networks in Engineered Tissues

“…(Nillesen et al, 2007) In addition, some of the molecules involved in the angiogenesis stabilization signaling pathways (Table 1) have been delivered to the target tissue together with stimuli involved in the initiation step. PDGF-BB, a signaling protein stimulating MC proliferation and recruitment, has been used in combined delivery with VEGF Richardson et al, 2001) and FGF-2 (Cao et al, 2003;Lu et al, 2007). Tested in many animal models, the dual delivery of PDGF-BB, a vessel maturation factor, with VEGF or FGF-2 resulted in not only an increase in vessel quantity, but also improved vessel quality.…”

“…Moreover, it allows long-term observation of vessel persistence. This method has only been used for evaluating growth factors or gene delivery, either as soluble factors (Cao et al, 2003;Lai et al, 2001;Lu et al, 2007) or immobilized in a hydrogel (Moon et al, 2010;Saik et al, 2010). Use of this model to evaluate cell therapies is still rare to our knowledge.…”