Cardiac fibrosis represented as perivascular/interstial fibrosis occurs in patients with hypertension. Oxidative stress has been demonstrated to contribute to such structural remodeling. The underlying mechanisms, however, remain to be elucidated. Herein, we tested the hypothesis that oxidative stress mediates cardiac fibrogenesis by stimulating transforming growth factor (TGF)-beta1 expression, which in turn triggers a series of fibrogenic responses. Sprague-Dawley rats were treated with angiotensin (Ang)II (9 microg/h s) for 4 weeks with/without co-treatment of combined antioxidants, apocynin, and tempol (120 mg/kg/day each, oral). Untreated rats served as controls. Appearance of cardiac oxidative stress and its potential effect on the expression of TGF-beta1, population of myofibroblasts, collagen synthesis/degradation, and fibrosis in hearts were examined. Chronic AngII infusion elevated systemic blood pressure (210 +/- 5 mmHg). Extensive perivascular and interstitial fibrosis was found in both ventricles, which were co-localized with oxidative stress represented as upregulated NADPH oxidase (gp91(phox) subunit) expression. Co-treatment with antioxidants led to: (1) markedly decreased cardiac gp91(phox); (2) significantly attenuated gene expression of TGF-beta1, type-I collagen, and tissue inhibitors of matrix metalloproteinase (TIMP)-I/II in the heart; (3) largely reduced population of myofibroblasts at sites of fibrosis; (4) significantly reduced cardiac collagen volume; (5) and partially suppressed blood pressure (190 +/- 4 mmHg). Thus, cardiac oxidative stress promotes the development of cardiac fibrosis by upregulating TGF-beta1 expression, which subsequently enhances cardiac collagen synthesis and suppresses collagen degradation in hypertensive rats.

The current study is to determine the regulatory role of VEGF-A in cardiac angiogenesis following myocardial infarction (MI). Cardiac angiogenic response and temporal/spatial expression of VEGF-A/VEGF receptors (VEGFR) were examined at 1, 2, 6, 12 hours and 1, 2, 3, 4, 7, 14, and 28 days postMI. We found that following MI, newly formed vessels first appeared at the border zone between noninfarcted and infarcted myocardium as early as day 3 and subsequently in the infarcted myocardium. Vascular density in the infarcted myocardium peaked at day 7 and then gradually declined. VEGF-A mRNA started to increase at the border zone at 2 hours postMI, reached peak at 12 hours, declined at day 1, and returned to normal levels at day 2 and thereafter. VEGF-A protein levels at the border zone were only increased during day 1 postMI. VEGF-A within the infarcted myocardium levels, however, were persistently suppressed postMI. VEGFR expression was significantly increased only at the border zone at day 1, but not in the later stages. The expression of VEGF-A/VEGFR remained unchanged in the noninfarcted myocardium. Thus, the early rise of VEGF-A/VEGFR at the border zone suggests that VEGF-A initiates the cardiac angiogenic response postMI, but short-lived VEGF-A/VEGFR activation at the border zone and consistently suppressed VEGF-A within the infarcted myocardium suggests that VEGF-A may not be crucial to the later stages of angiogenesis.

Aims Cardiac remodeling occurs in the infarcted heart (MI). The underlying regulatory mechanisms are under investigation. Platelet-derived growth factor (PDGF) is a family of growth factors that stimulates cell growth, differentiation and migration. Herein, we sought to determine whether PDGF is involved in cardiac repair/remodeling following MI. Methods and Results The temporal and spatial expression of PDGF isoforms (A, B, C and D) and PDGF receptor (PDGFR)-α and β as well as cell types expressing PDGF were examined in the infarcted rat heart. Sham-operated rats served as controls. We found that the normal myocardium expressed all PDGF isoforms, and cell types expressing PDGF were primarily interstitial cells. Following MI, PDGF-A and D were significantly increased in the infarcted myocardium during 6 weeks of the observation period and cells expressing PDGF-A and D were primarily endothelial cells, macrophages and myofibroblasts (myoFb). PDGF-B and C expression was, however, reduced in the infarcted heart. In the noninfarcted myocardium, PDGF-D expression was increased in the late stage of MI and cells expressing PDGF-D were predominantly fibroblasts. Both PDGFR-α and β were significantly increased in the infarcted myocardium in the early and late stages of MI and in the noninfarcted myocardium in the late stage of MI. Conclusions Enhanced PDGF-A, PDGF-D and PDGFR are coincident with angiogenesis, inflammatory and fibrogenic responses in the infarcted myocardium, suggesting their regulation on cardiac repair. Elevated PDGF-D in the noninfarcted myocardium suggests its involvement in the development of interstitial fibrosis that appears in the late stage of MI.

Background Angiogenesis is crucial for many pathological processes and becomes a therapeutic strategy against diseases ranging from inflammation to cancer. The regulatory mechanism of angiogenesis remains unclear. Although tetraspanin CD82 is widely expressed in various endothelial cells (ECs), its vascular function is unknown. Methods and Results Angiogenesis was examined in Cd82-null mice with in vivo and ex vivo morphogenesis assays. Cellular functions, molecular interactions, and signaling were analyzed in Cd82-null ECs. Angiogenic responses to various stimuli became markedly increased upon Cd82 ablation. Major changes of Cd82-null ECs were enhanced migration and invasion, likely resulting from the upregulated expression of cell adhesion molecules (CAMs) such as CD44 and integrins at the cell surface and subsequently elevated outside-in signaling. Gangliosides, lipid raft clustering, and CD44-membrane microdomain interactions were increased in the plasma membrane of Cd82-null ECs, leading to less clathrin-independent endocytosis and then more surface presence of CD44. Conclusions Our study reveals that CD82 restrains pathological angiogenesis by inhibiting EC movement, lipid raft clustering and CAM trafficking modulate angiogenic potential, and the perturbation of CD82-ganglioside-CD44 signaling attenuates angiogenesis.

Both the activation of the renin angiotensin aldosterone system (RAAS) and elevations of circulating Fibroblast Growth Factor-23 (FGF-23) have been implicated in the pathogenesis of left ventricular hypertrophy (LVH) in chronic kidney disease. To investigate potential cross-talk between RAAS and FGF-23, we administered angiotensin II (Ang II) to wild-type rodents and the Hyp mouse model of excess FGF-23. Ang II administration for four weeks to wild-type rodents resulted in significant increases in systolic blood pressure and LVH. Unexpectedly, FGF-23 circulating levels were increased by 1.5–1.7 fold in Ang II treated animals. In addition, Ang II treatment increased expression of FGF-23 message levels in bone, the predominant tissue for FGF-23 production, and induced expression of FGF-23 and its co-receptor α-Klotho in the heart, which normally does not express FGF-23 or α-Klotho in physiologically relevant levels. Hyp mice with elevated FGF-23 exhibited increased blood pressure and LVH at baseline. Ang II administration to Hyp mice resulted further increments in blood pressure and left ventricular hypertrophy, consistent with additive cardiovascular effects. These findings suggest that FGF-23 may participate in unexpected systemic and paracrine networks regulating hemodynamic and myocardial responses.