Our results suggest that NO plays a minimal role in vasodilation at peak RH but plays a modest yet significant role in maintaining vasodilation after peak vasodilation. Our results also suggest that reactive hyperemia in human forearms is caused largely by mechanisms other than NO.
Mammalian spermatogenesis-the transformation of stem cells into millions of haploid spermatozoa-is elaborately organized in time and space. We explored the underlying regulatory mechanisms by genetically and chemically perturbing spermatogenesis in vivo, focusing on spermatogonial differentiation, which begins a series of amplifying divisions, and meiotic initiation, which ends these divisions. We first found that, in mice lacking the retinoic acid (RA) target gene Stimulated by retinoic acid gene 8 (Stra8), undifferentiated spermatogonia accumulated in unusually high numbers as early as 10 d after birth, whereas differentiating spermatogonia were depleted. We thus conclude that Stra8, previously shown to be required for meiotic initiation, also promotes (but is not strictly required for) spermatogonial differentiation. Second, we found that injection of RA into wild-type adult males induced, independently, precocious spermatogonial differentiation and precocious meiotic initiation; thus, RA acts instructively on germ cells at both transitions. Third, the competencies of germ cells to undergo spermatogonial differentiation or meiotic initiation in response to RA were found to be distinct, periodic, and limited to particular seminiferous stages. Competencies for both transitions begin while RA levels are low, so that the germ cells respond as soon as RA levels rise. Together with other findings, our results demonstrate that periodic RA-STRA8 signaling intersects with periodic germ-cell competencies to regulate two distinct, cell-type-specific responses: spermatogonial differentiation and meiotic initiation. This simple mechanism, with one signal both starting and ending the amplifying divisions, contributes to the prodigious output of spermatozoa and to the elaborate organization of spermatogenesis.spermatogenesis | Stra8 | mouse | retinoic acid | testis
SignificanceMale mouse sex cells mature into sperm through a 35-d process punctuated by four transitions, two occurring before meiosis (spermatogonial differentiation and meiotic initiation) and two after meiosis (spermatid elongation and sperm release). The four transitions occur in proximity spatially and temporally, with an 8.6-d periodicity. We describe how this coordination is achieved. The premeiotic transitions were known to be regulated by retinoic acid (RA). We show that RA also regulates the two postmeiotic transitions. RA levels change periodically, and meiotic cells contribute to its production. The two postmeiotic transitions require RA from meiotic cells while the premeiotic transitions require RA from somatic cells. These elements underpin the spatiotemporal coordination of spermatogenesis to ensure constant sperm production throughout adult life.
Our results suggest that L-NMMA decreased FBF after exercise largely by decreasing resting FBF. These results suggest that NO may not play a significant role in exercise-induced metabolic arteriolar vasodilation in the forearm of healthy humans.
Nuclear core histone modifications influence chromosome structures and functions. Recently, the involvement of histone acetylations in the cell memory of gene expression has been suggested in mouse oocyte maturation. At present, there is little available data on histone modifications in mammalian oocyte maturation. In the present study, we examined changes in the acetylation of histone H3 lysines 9 (H3K9) and 14 (H3K14), and histone H4 lysines 5 (H4K5), 8 (H4K8) and 12 (H4K12), and trimethylation of H3K9 during in vitro maturation of porcine oocytes. Immunocytochemical analyses revealed that the all of the lysines examined were highly acetylated in the germinal vesicle stage, and this level of acetylation was maintained until the first prometaphase. In the first metaphase, the lysines near the N-terminal end, H3K9 and H4K5, were completely deacetylated. The acetylation of the lysines far from the N-terminal end, H3K14, H4K8, and H4K12, was markedly decreased but still present. The acetylations were increased transiently at the first anaphase and telophase, and then decreased again at the second metaphase to the same level as the first metaphase. Since effective concentrations of trichostatin A (TSA) to inhibit the deacetylation were different in various lysine residues, multiple histone deacetylases (HDACs) were suggested to function during meiotic maturation. The trimethylation of H3K9 was maintained in a high level throughout maturation. These results suggest that the histone acetylation during porcine oocyte maturation is precisely controlled by the cell cycle.
Nitric oxide (NO) is shown to be synthesized in the central nervous system as well as in vascular endothelial cells. However, the physiological role of NO in cardiovascular regulation in the central nervous system remains unclear. The present study examines whether NO plays a role in the regulation of neuronal activity in the nucleus tractus solitarius (NTS). Single-unit extracellular recordings were obtained from NTS neurons in slices (400 microns) of the rat brainstem, which had spontaneous discharges at a frequency of 0.5 to 3 spikes per second. Eighty-one neurons were tested for sensitivity to L-arginine, which is the physiological precursor of NO. L-Arginine (10(-7) to 10(-4) mol/L) increased neuronal activity dose dependently in 33 (40.7%) of 81 neurons tested, but D-arginine (10(-5) mol/L) did not. The neurons that responded to L-arginine responded to glutamate as well. NG-Monomethyl-L-arginine (10(-5) to 3 x 10(-5) mol/L), an inhibitor of the formation of NO, dose-dependently blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Hemoglobin (1.5 mg/L), a trapper of NO, and methylene blue (10(-5) mol/L), an inhibitor of guanylate cyclase, also blocked increases in the neuronal activity evoked with L-arginine (10(-5) mol/L). Sodium nitroprusside (SNP, 10(-5) to 10(-4) mol/L), which spontaneously produces NO, increased the neuronal activity in the neurons that responded to L-arginine. SNP did not alter the neuronal activity of the neurons that did not respond to L-arginine.(ABSTRACT TRUNCATED AT 250 WORDS)
Our results suggest that defective endothelial function may contribute to impaired ischemic vasodilator capacity in HF.
Retinoic acid (RA), a derivative of vitamin A, is critical for the production of oocytes and sperm in mammals. These gametes derive from primordial germ cells, which colonize the nascent gonad, and later undertake sexual differentiation to produce oocytes or sperm. During fetal development, germ cells in the ovary initiate meiosis in response to RA, whereas those in the testis do not yet initiate meiosis, as they are insulated from RA, and undergo cell cycle arrest. After birth, male germ cells resume proliferation and undergo a transition to spermatogonia, which are destined to develop into haploid spermatozoa via spermatogenesis. Recent findings indicate that RA levels change periodically in adult testes to direct not only meiotic initiation, but also other key developmental transitions to ensure that spermatogenesis is precisely organized for the prodigious output of sperm. This review focuses on how female and male germ cells develop in the ovary and testis, respectively, and the role of RA in this process.
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