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Vascular development is a complex but orderly process that is tightly regulated. A number of secreted factors produced by surrounding cells regulate endothelial cell (EC) differentiation, proliferation, migration and coalescence into cord-like structures. Vascular cords then undergo tubulogenesis to form vessels with a central lumen. But little is known about how tubulogenesis is regulated in vivo. Here we report the identification and characterization of a new EC-derived secreted factor, EGF-like domain 7 (Egfl7). Egfl7 is expressed at high levels in the vasculature associated with tissue proliferation, and is downregulated in most of the mature vessels in normal adult tissues. Loss of Egfl7 function in zebrafish embryos specifically blocks vascular tubulogenesis. We uncover a dynamic process during which gradual separation and proper spatial arrangement of the angioblasts allow subsequent assembly of vascular tubes. This process fails to take place in Egfl7 knockdown embryos, leading to the failure of vascular tube formation. Our study defines a regulator that controls a specific and important step in vasculogenesis.

Cigarette smoking increased during alcohol self-administration in comparison to an alcohol-free baseline in 24 women given access to alcohol for 21 days. Heavy smokers (25 or more cigarettes per day) increased smoking significantly during drinking (P less than 0.05). Analysis of tobacco smoking by level of alcohol consumption showed that both heavy and moderate alcohol users increased smoking significantly during alcohol availability (P less than 0.05, 0.01). The heavy and moderate smokers smoked significantly more between noon and midnight (P less than 0.001) than at other times when alcohol was available. The rate of cigarette smoking (defined by inter-cigarette intervals) was faster during alcohol self-administration than during the alcohol-free baseline. Heavy smokers smoked most cigarettes at intervals of 11-20 min during heavy or moderate drinking. During the pre-alcohol baseline, these women smoked most cigarettes at intervals of 21-30 or 31-40 min. Most women (70-74%) also increased tobacco smoking at the premenstruum. Both heavy and occasional smokers increased smoking at the premenstruum significantly more than the moderate smokers (P less than 0.05). All women reported increased psychological discomfort at the premenstruum on the Premenstrual Assessment Form (PAF) but reports of physical discomfort were more marked in women who smoked less at the premenstruum. These data extend previous findings in men that alcohol consumption is associated with increased cigarette smoking to female social drinkers.

To help elucidate the mechanisms by which nerve growth factor (NGF) regulates gene expression, we have identified and studied four genes (a-2, d-2, d4, and d-S) that are positively regulated by NGF in PC12 cells, including one (d-2) which has previously been identified as a putative transcription factor (NGF I-A). Three of these genes, including d-2, were induced very rapidly at the transcriptional level, but the relative time courses of transcription and mRNA accumulation of each of these three genes were distinct. The fourth gene (d4) displayed no apparent increase in transcription that corresponded to the increase in its mRNA, suggesting that NGF may regulate its expression at a posttranscriptional level. Thus, NGF positively regulates gene expression by more than one mechanism. These genes could also be distinguished on the basis of their response to cyclic AMP. The expression of d-2 and a-2 was increased by cholera toxin and further augmented by NGF; however, cholera toxin not only failed to increase the levels of d-5 and d4 mRNA but also actually inhibited the NGF-dependent increase. The expression of each of these genes, including d-2 (NGF I-A), was also increased by fibroblast growth factor, epidermal growth factor (EGF), phorbol myristate acetate, and in some cases insulin, showing that the regulation of these genes is not unique to NGF. Because each of these genes was expressed in response to phorbol myristate acetate and EGF, their expression may be necessary but is certainly not sufficient for neurite formation. The protein kinase inhibitor K-252a prevented the NGF-associated, but not the acidic FGF-associated, induction of d-2 and d-5 gene expression, suggesting that these two growth factors may regulate gene expression via different cellular pathways. The study of the regulation of the expression of these and other NGF-inducible genes should provide valuable new information concerning how NGF and other growth factors cause neural differentiation.Nerve growth factor (NGF) is a peptide hormone that is essential for the development and the survival of sympathetic nerves, sensory nerves, and certain populations of nerves in the central nervous system (32,52). It also influences many aspects of cell metabolism, including RNA synthesis, protein synthesis, protein phosphorylation, and ion flux (1,11,22,46,54). However, studies of NGF action on neural differentiation have been hampered because NGF influences both cell survival and cell differentiation.PC12 cells, a cloned line derived from a rat pheochromocytoma, has been a useful model system for studying NGFdependent differentiation (18). Although NGF is not required as a survival factor for these cells, it retains the ability to stimulate differentiation and process formation. The heparinbinding peptide growth factors, acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF), also stimulate neurite outgrowth and differentiation in PC12 cells in a pattern that is not distinguishable from that of NGF (47, 51). In the presence of NG...

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