NM, Herring CM, Tan J, Lahm T, Meldrum DR. VEGF is critical for stem cell-mediated cardioprotection and a crucial paracrine factor for defining the age threshold in adult and neonatal stem cell function.

Mesenchymal stem cells (MSCs) are a promising therapy for acute organ ischemia in part due to their paracrine production of growth factors. However, transplanted cells encounter an inflammatory environment that mitigates their function and survival, and treating the cells with exogenous agents during ex vivo expansion before transplantation is one strategy for overcoming this limitation by enhancing paracrine function. We hypothesized that preconditioning bone marrow MSCs with TGF-alpha would 1) increase MSC production of the critical paracrine factor, vascular endothelial growth factor (VEGF), via a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism and 2) enhance myocardial functional recovery in a rat model of acute myocardial I/R injury. To study this, bone marrow MSCs were harvested from adult male mice (C57BL/6J) and treated in vitro for 24 h according to the following groups: 1) control, 2) TGF-alpha (250 ng mL (-1)), 3) TNF-alpha (50 ng mL (-1)), 4) TGF-alpha + TNF-alpha, 5) hypoxia, and 6) TGF-alpha + hypoxia. For the isolated heart perfusion experiments, adult male Sprague-Dawley rat hearts were isolated, perfused via the Langendorff model, and subjected to I/R. Vehicle or MSCs with or without TGF-alpha preconditioning were infused immediately before ischemia. Mesenchymal stem cells were also treated with TGF-alpha alone or in combination with a p38 MAPK inhibitor (SB202190). In vitro, TGF-alpha increased MSC VEGF production alone (157.9 +/- 1.11 - 291.0 +/- 3.74 pg 10 (-5); P < 0.05) and, to a greater extent, in combination with TNF-alpha or hypoxia (364.5 +/- 0.868 and 342.0 +/- 7.92 pg 10(-5) cells, respectively; P < 0.05 vs. TGF-alpha alone). Postischemic myocardial functional recovery was greater in hearts infused with TGF-alpha-preconditioned MSCs compared with untreated MSCs or vehicle. Myocardial IL-1beta and TNF-alpha production and activation of caspase 3 were significantly decreased after infusion of both cell groups. p38 MAPK inhibition suppressed TGF-alpha-stimulated MSC VEGF production and postischemic myocardial recovery. These results suggest that TGF-alpha stimulates MSC VEGF production in part via a p38 MAPK-dependent mechanism, and preconditioning MSCs with TGF-alpha may enhance their ability to protect myocardium during I/R injury.

Females have a lower incidence of heart failure and improved survival after myocardial ischemia-reperfusion (I/R) compared with males. Although estrogen-suppressed cardiomyocyte apoptosis may be mediated through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, it is unclear whether this action is mediated via estrogen receptor beta (ERbeta). Therefore, we hypothesized that ERbeta mediates estrogen-induced cardioprotection through PI3K/Akt and antiapoptotic signaling in females but not in males. Isolated male and female hearts from ERbeta knockout (ERbetaKO) and wild-type (WT) mice (n = 5 mice/group) were subjected to 20-min ischemia followed by 60-min reperfusion (Langendorff). Ablation of ERbeta significantly decreased postischemic recovery of left ventricular developed pressure in female, but not male, hearts. Reduced activation of PI3K and Akt was noted in female ERbetaKO hearts, which was associated with increased expression of caspase-3 and -8, as well as decreased Bcl-2 levels compared with WT. However, myocardial STAT3, SOCS3 (suppressor of cytokine signaling 3), VEGF, and TNF receptors 1 and 2 levels did not change in ERbetaKO of either sex following I/R. Furthermore, deficiency of ERbeta increased myocardial JNK activation in females but increased ERK1/2 activity in males during acute I/R. We conclude that ERbeta mediates myocardial protection via upregulation of PI3K/Akt activation, decreased caspase-3 and -8, and increased Bcl-2 in female hearts following I/R. These findings provide evidence of ERbeta-mediated PI3K/Akt and antiapoptotic signaling in the myocardium and may lend insight into the mechanistic pathways behind the observed variation in clinical outcomes between males and females after myocardial infarction.

Objectives Type 2 endoleaks are common after endovascular aneurysm repair (EVAR) but their clinical significance remains undefined and their management controversial. We determined risk factors for type 2 endoleak and associations with adverse outcomes. Methods We identified all EVAR patients in the Vascular Study Group of New England abdominal aortic aneurysm (AAA) database. Patients were subdivided into two groups: 1) those with no endoleak or transient type 2 endoleak and 2) persistent type 2 endoleak or new type 2 endoleak (no endoleak at completion of case). Patients with other endoleak types and follow-up shorter than 6 months were excluded. Multivariable analysis was used to evaluate predictors of persistent or new type 2 endoleaks. Kaplan-Meier and Cox regression analysis were used to evaluate predictors of reintervention and survival. Results 2367 EVAR patients had information on endoleaks; 1977 (84%) were in group 1, of which 79% had no endoleak at all and 21% were transient endoleaks that resolved at follow-up. The other 390 (16%) were in group 2, of which 31% had a persistent leak and 69% had a new leak at follow-up that was not seen at the time of surgery. Group 2 was older (mean age 75 vs. 73 years, P<.001), and less likely to have COPD (24% vs. 34%, P<.001) or elevated creatinine levels (2.6% vs. 5.3%, P=0.027). Coil embolization of one or both hypogastric arteries was associated with a higher rate of persistent type 2 endoleaks (12 vs. 8%, P=0.024), as was distal graft extension (12% vs. 8%, P=0.008). In multivariable analysis, COPD (OR 0.7, 95% CI 0.5–0.9, P=0.017) was protective against persistent type 2 endoleak, while hypogastric artery coil embolization (OR 1.5, 95% CI 1.0–2.2, P=0.044), distal graft extension (OR 1.6, 95% CI 1.1–2.3, P=0.025) and age ≥ 80 (OR 2.7, 95% CI 1.4–5.3, P=0.004) were predictive. Graft type was also associated with endoleak development. Persistent type 2 endoleaks were predictive of post-discharge reintervention (OR 15.3, 95% CI 9.7–24.3, P<.001), however not predictive of long-term survival (OR 1.1, 95%CI 0.9–1.6, P=0.477). Conclusion Persistent type 2 endoleak is associated with hypogastric artery coil embolization, distal graft extension, older age, the absence of COPD, and graft type, but not with aneurysm size. Persistent type 2 endoleaks are associated with an increased risk of reinterventions, but not rupture or survival. This reinforces the need for continued surveillance of patients with persistent type 2 endoleaks and the importance of follow-up to detect new type 2 endoleaks over time.

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