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Background
Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disorder with a poor prognosis [1]. The disease is characterized by pulmonary vasoconstriction and increased pulmonary vascular resistance, which lead to right ventricular failure, fluid overload, and death [2]. The major histopathological features of PAH are vascular wall remodeling, in situ thrombosis, endothelial cell dysfunction and pulmonary artery smooth muscle cell (PASMC) proliferation [2, 3]. In Asian countries, PAH occurs in nearly 2 persons per 1,000,000 person-years, and PAH-related mortality occurs in 7 persons per 100 person-years [4]. However, the mechanism underlying the development of this disorder remains unknown. Increasing evidence suggests that treatments with anti-inflammatory effects, as well as treatments that can reverse cell proliferation, may be helpful for the management of PAH, but these approaches require further study.
Extracellular adenosine has anti-oxidant and anti-inflammatory properties and mediates a variety of physiological processes, including systemic vascular vasodilation and human pulmonary vessel regulation [5, 6]. The effects of adenosine are mediated by four cellular adenosine receptors: A1, A2A, A2B, and A3 [7]. Of these, the A2A receptor (A2AR) is recognized as an important mediator of inflammatory and immune responses [8]. The A2AR is activated by adenosine or agonists, such as CGS21680, and initiates negative-feedback mechanisms that inhibit systemic inflammatory responses [9]. The chemokine stromal cell-derived factor-1 (SDF-1), also named CXCL12, belongs to the C-X-C chemokine subfamily. SDF-1 exerts an effective function through binding to its specific receptor, CXC chemokine receptor type 4 (CXCR4) [10]. The SDF-1/CXCR4 signaling system plays a crucial role in hematopoiesis, cardiogenesis, and vasculogenesis [11]. Specifically, the SDF-1/CXCR4 axis plays an important role in vascular remodeling. Recent evidence shows that inhibiting the SDF-1/CXCR4 axis attenuates hypoxia-induced PAH in neonatal mice by reversing pulmonary vascular cell proliferation [12]. Moreover, A2AR activation reportedly suppresses chemokine receptor function via heterologous desensitization, thereby enhancing the anti-inflammatory effects of adenosine [13]. Therefore, we investigated whether A2AR signaling affects the SDF-1/CXCR4 axis in PAH using A2AR knockout (A2AR?/?) mice. We hypothesized that A2AR activation may have a beneficial effect on PAH by down-regulating the SDF-1/CXCR4 axis. SDF-1/CXCR4 signaling triggers cell proliferation and anti-apoptosis pathways, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB; AKT) and mitogen-activated protein kinase (MAPK/ERK) pathways [14]. PI3Ks are a subfamily of lipid kinases that...