Interactions of adult neural stem cells (NSCs) with supportive vasculature appear critical for their maintenance and function, although the molecular details are still under investigation. Neurotrophin (NT)-3 belongs to the NT family of trophic factors, best known for their effects in promoting neuronal survival. Here we show that NT-3 produced and secreted by endothelial cells of brain and choroid plexus capillaries is required for the quiescence and long-term maintenance of NSCs in the mouse subependymal niche. Uptake of NT-3 from irrigating vasculature and cerebrospinal fluid (CSF) induces the rapid phosphorylation of endothelial nitric oxide (NO) synthase present in the NSCs, leading to the production of NO, which subsequently acts as a cytostatic factor. Our results identify a novel interaction between stem cells and vasculature/CSF compartments that is mediated by an unprecedented role of a neurotrophin and indicate that stem cells can regulate their own quiescence in response to endothelium-secreted molecules.

. Different expression of adrenoceptors and GRKs in the human myocardium depends on heart failure ethiology and correlates to clinical variables. Am J Physiol Heart Circ Physiol 303: H368 -H376, 2012. First published June 8, 2012; doi:10.1152/ajpheart.01061.2011.-Downregulation of ␤ 1-adrenergic receptors (␤ 1-ARs) and increased expression/function of G-protein-coupled receptor kinase 2 (GRK2) have been observed in human heart failure, but changes in expression of other ARs and GRKs have not been established. Another unresolved question is the incidence of these compensatory mechanisms depending on heart failure etiology and treatment. To analyze these questions, we quantified the mRNA/protein expressions of six ARs (␣ 1A, ␣1B, ␣1D, ␤1, ␤ 2, and ␤3) and three GRKs (GRK2, GRK3, and GRK5) in left (LV) and right ventricle (RV) from four donors, 10 patients with ischemic cardiomyopathy (IC), 14 patients with dilated cardiomyopathy (DC), and 10 patients with nonischemic, nondilated cardiopathies (NINDC). We correlated the changes in the expressions of ARs and GRKs with clinical variables such as left ventricular ejection fraction (LVEF) and left ventricular end-systolic and left ventricular end-diastolic diameter (LVESD and LVEDD, respectively). The main findings were 1) the expression of the ␣ 1A-AR in the LV positively correlates with LVEF; 2) the expression of GRK3 and GRK5 inversely correlates with LVESD and LVEDD, supporting previous observations about a protective role for both kinases in failing hearts; and 3) ␤ 1-AR expression is downregulated in the LV and RV of IC, in the LV of DC, and in the RV of NINDC. This difference, better than an increased expression of GRK2 (not observed in IC), determines the lower LVEF in IC and DC vs. NINDC. G-protein-coupled receptor kinasesHUMAN HEART FAILURE (HF) is recognized as a major public health problem arising from multiple causes that will affect one in five adults, conferring elevated mortality rates (20). Regardless of the cause, multiple organ systems attempt to compensate for the deteriorating heart and the sympathetic nervous system responds to HF with increased activity, resulting in increased levels of catecholamines and in an enhanced stimulation of adrenergic receptors (ARs; 33). Consequently, catecholamines powerfully stimulate the heart function at the expense of overproportional increases in energy consumption (13). This is a nonrigid signaling system that adapts to continuous stimulation by reducing the abundance of ␤ 1 -ARs and increasing the expression and enzymatic activity of G-proteincoupled receptor kinases (GRKs), which phosphorylate agonist-occupied receptors and facilitate their endocytosis and desensitization (26). As a result of these adaptations, cardiomyocytes in failing hearts (FH) lose their responsiveness to catecholamines over time (13).In spite of this simple scenario, many fundamental questions remain unanswered. The heart expresses different ␤-ARs (␤ 1 , ␤ 2 , and ␤ 3 ) and ␣ 1 -ARs (␣ 1A , ␣ 1B , and ␣ 1D

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To explore if genic expression of β(1)- or β(2)-adrenoceptors (ARs) exhibits a common regulatory pattern with G protein-coupled receptor kinase (GRK) 2, GRK3, or GRK5 expression, we determined messenger RNA levels for these genes in different tissues from human and animal models of cardiovascular disease. We measured genic expression by qRT polymerase chain reaction in the left and right ventricles or peripheral blood mononuclear cells from healthy (n = 21), hypertensive (n = 20), heart failure (n = 24), and heart transplanted patients (n = 17) or in left ventricle, peripheral blood mononuclear cells, and kidney from spontaneously hypertensive rats or L-N-methyl-arginine-induced hypertensive rats and their respective controls (n = 4-5). In diseased versus healthy subjects and rats, parallel changes in messenger RNA levels of GRK2 and β(2)-AR or GRK5 and β(1)-AR were observed in each territory. Therefore, without excluding other regulatory mechanisms, the parallelism observed suggests a common regulatory pattern for the β(1)-AR/GRK5 and β(2)-AR/GRK2 genes, which is independent of cellular type or pathology. This highlights the need to focus not only on GRKs but also on β(1)- or β(2)-AR changes to completely understand the involvement of β-AR/GRK pathways in cardiovascular diseases.

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