We have isolated and characterized a novel growth factor for endothelial cells,

Since high-affinity adenosine A2 receptors (A2u) are localized exclusively in dopamine-rich regions in the central nervous system and mediate inhibition of locomotor activity, we have examined the effect of A2 receptor activation on D1 and D2 receptor binding in membrane preparations of the rat striatum. The A2a agonist 2-p-(2-carboxyethyl)phen- ethylaminoJ-5'-N-ethylcarboxamidoadenosine (CGS 21680) Adenosine has been shown to function as a neuromodulator in many areas of the mammalian central nervous system (1-3). These actions of adenosine are mediated by receptors that can be subdivided into Al and A2 subtypes based on relative agonist and antagonist potencies (4, 5). Al activation inhibits and A2 activation stimulates adenylate cyclase (4, 6, 7). The A2 receptors have been further subclassified into high-affinity (A2a) and low-affinity (A2b) receptors, based on agonist potencies with regard to adenylate cyclase activation (4) and receptor binding (5). The A2b receptors are widely distributed in the brain and mediate the stimulatory action of high concentrations of adenosine agonists on cAMP formation, which could affect dopamine release and synthesis (8,9). In contrast, A2a receptors are exclusively localized to dopamine-innervated areas ofthe central nervous system (10, 11), with a postsynaptic distribution (12) similar to that of postsynaptic D1 and D2 receptors (13). By using in situ hybridization the recently cloned A2a receptors (14) have been found to be localized to striatal medium-sized neurons (15).Adenosine agonists inhibit, whereas adenosine antagonists, including caffeine, enhance spontaneous (16, 17) and dopamine-induced locomotor activity (16,(18)(19)(20). The potencies of adenosine agonists in producing hypomotility correlate with their affinities for Au adenosine receptors (21,22), suggesting that A2. receptors mediate most of the behavioral effects of adenosine agonists. The hypomotility induced by adenosine agonists resembles that induced by classical neuroleptics (22), which act by blocking postsynaptic D2 receptors (23). In fact, behavioral evidence for a negative interaction between postsynaptic A2. and D2 receptors has recently been obtained using acutely reserpinized mice (24,25). Since activation of postsynaptic D2 receptors seems to be a necessary step for locomotor behavior, a negative interaction between postsynaptic A2. and D2 receptors could explain the hypomotility induced by adenosine agonists and the enhancement of locomotor activity induced by adenosine antagonists, including caffeine (24,25).In contrast to the A2a receptor, the D2 receptor mediates an inhibition of adenylate cyclase (26

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The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2 0 -deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.

VEGF-B seems to be required for normal heart function in adult animals but is not required for proper development of the cardiovascular system either during development or for angiogenesis in adults.

A second isoform and the genomic structures of mouse and human vascular endothelial growth factor B are described. Both genes consist of seven coding exons and span about 4 kilobases of DNA. The two identified isoforms of vascular endothelial growth factor B are generated by alternative splicing where different splice acceptor sites in exon 6 introduce a frameshift and a partial use of different but overlapping reading frames. Consequently, the COOH-terminal domains in the two isoforms show no resemblance. Mouse and human cDNA clones for the novel isoform of vascular endothelial growth factor B encoded a secreted protein of 186 amino acid residues. Expression in transfected cells generated a protein of 25 kDa which upon secretion was modified by O-linked glycosylation and displayed a molecular mass of 32 kDa under reducing conditions. The protein was expressed as a disulfide-linked homodimer, and heterodimers were generated when coexpressed with vascular endothelial growth factor. The entirely different COOH-terminal domains in the two isoforms of vascular endothelial growth factor B imply that some functional properties of the two proteins are distinct.

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