Cerebral artery reactivity changes during pregnancy and the postpartum period: a role in eclampsia?

Eclampsia is thought to be similar to hypertensive encephalopathy, whereby acute elevations in intravascular pressure cause forced dilatation (FD) of intrinsic myogenic tone of cerebral arteries and arterioles, decreased cerebrovascular resistance, and hyperperfusion. In the present study, we tested the hypothesis that pregnancy and/or the postpartum period predispose cerebral arteries to FD by diminishing pressure-induced myogenic activity. We compared the reactivity to pressure (myogenic activity) as well as factors that modulate the level of tone of third-order branches (<200 microm) of the posterior cerebral artery (PCA) that were isolated from nonpregnant (NP, n = 7), late-pregnant (LP, 19 days, n = 10), and postpartum (PP, 3 days, n = 8) Sprague-Dawley rats under pressurized conditions. PCAs from all groups of animals developed spontaneous tone within the myogenic pressure range (50-150 mmHg) and constricted arteries at 100 mmHg (NP, 30 +/- 3; LP, 39 +/- 4; and PP, 42 +/- 7%; P > 0.05). This level of myogenic activity was maintained in the NP arteries at all pressures; however, both LP and PP arteries dilated at considerably lower pressures compared with NP, which lowered the pressure at which FD occurred from >175 for NP to 146 +/- 6.5 mmHg for LP (P < 0.01 vs. NP) and 162 +/- 7.7 mmHg for PP (P < 0.01 vs. NP). The amount of myogenic tone was also significantly diminished at 175 mmHg compared with NP: percent tone for NP, LP, and PP animals were 35 +/- 2, 11 +/- 3 (P < 0.01 vs. NP), and 20 +/- 7% (P < 0.01 vs. NP), respectively. Inhibition of nitric oxide (NO) with 0.1 mM N(omega)-nitro-l-arginine (l-NNA) caused constriction of all vessel types that was significantly increased in the PP arteries, which demonstrates significant basal NO production. Reactivity to 5-hydroxytryptamine (serotonin) was assessed in the presence of l-NNA and indomethacin. There was a differential response to serotonin: PCAs from NP animals dilated, whereas LP and PP arteries constricted. These results suggest that both pregnancy and the postpartum period predispose the cerebral circulation to FD at lower pressures, a response that may lower cerebrovascular resistance and promote hyperperfusion when blood pressure is elevated, as occurs during eclampsia.     

Estradiol, progesterone and prolactin modulate mammary gland morphogenesis in adult female plains vizcacha (Lagostomus maximus)

We studied for the first time the mammary gland morphogenesis and its hormonal modulation by immunolocalizing estradiol, progesterone and prolactin receptors (ER, PR and PRLR) in adult females of Lagostomus maximus, a caviomorph rodent which shows a pseudo-ovulatory process at mid-gestation. Mammary ductal system of non-pregnant females lacks expression of both ERα and ERβ. Yet throughout pregnancy, ERα and ERβ levels increase as well as the expression of PR. These increments are concomitant with ductal branching and alveolar differentiation. Even though mammary gland morphology is quite similar to that described for other rodents, alveolar proliferation and differentiation are accelerated towards the second half of pregnancy, once pseudo-ovulation had occurred. Moreover, this exponential growth correlates with an increment of both progesterone and estradiol serum-induced pseudo-ovulation. As expected, PR and PRLR are strongly expressed in the alveolar epithelium during pregnancy and lactation. Strikingly, PRLR is also present in ductal epithelia of cycling glands suggesting that prolactin function may not be restricted to its trophic effect on mammary glands of pregnant and lactating females, but it also regulates other physiological processes in mammary glands of non-pregnant animals. In conclusion, this report suggests that pseudo-ovulation at mid-gestation may be associated to L. maximus mammary gland growth and differentiation. The rise in P and E2-induced pseudo-ovulation as well as the increased expression of their receptors, all events that correlate with the development of a more elaborated and differentiated ductal network, pinpoint a possible relation between this peculiar physiological event and mammary gland morphogenesis.     

Atomistic details of effect of disulfide bond reduction on active site of Phytase B from Aspergillus niger: A MD Study

The molecular integrity of the active site of phytases from fungi is critical for maintaining phytase function as efficient catalytic machines. In this study, the molecular dynamics (MD) of two monomers of phytase B from Aspergillus niger, the disulfide intact monomer (NAP) and a monomer with broken disulfide bonds (RAP), were simulated to explore the conformational basis of the loss of catalytic activity when disulfide bonds are broken. The simulations indicated that the overall secondary and tertiary structures of the two monomers were nearly identical but differed in some crucial secondary–structural elements in the vicinity of the disulfide bonds and catalytic site. Disulfide bonds stabilize the β-sheet that contains residue Arg66 of the active site and destabilize the α-helix that contains the catalytic residue Asp319. This stabilization and destabilization lead to changes in the shape of the active–site pocket. Functionally important hydrogen bonds and atomic fluctuations in the catalytic pocket change during the RAP simulation. None of the disulfide bonds are in or near the catalytic pocket but are most likely essential for maintaining the native conformation of the catalytic site.

Abbreviations

PhyB - 2.5 pH acid phophatese from Aspergillus niger, NAP - disulphide intact monomer of Phytase B, RAP - disulphide reduced monomer of Phytase B, Rg - radius of gyration, RMSD - root mean square deviation, MD - molecular dynamics.     

Effect of weight loss and exercise on angiogenic factors in the circulation and in adipose tissue in obese subjects

Background:

Vascular growth is a prerequisite for adipose tissue (AT) development and expansion. Some AT cytokines and hormones have effects on vascular development, like vascular endothelial growth factor (VEGF‐A), angiopoietin (ANG‐1), ANG‐2 and angiopoietin‐like protein‐4 (ANGPTL‐4).

Methods:

In this study, the independent and combined effects of diet‐induced weight loss and exercise on AT gene expression and proteins levels of those angiogenic factors were investigated. Seventy‐nine obese males and females were randomized to: 1. Exercise‐only (EXO; 12‐weeks exercise without diet‐restriction), 2. Hypocaloric diet (DIO; 8‐weeks very low energy diet (VLED) + 4‐weeks weight maintenance diet) and 3. Hypocaloric diet and exercise (DEX; 8‐weeks VLED + 4‐weeks weight maintenance diet combined with exercise throughout the 12 weeks). Blood samples and fat biopsies were taken before and after the intervention.

Results:

Weight loss was 3.5 kg in the EXO group and 12.3 kg in the DIO and DEX groups. VEGF‐A protein was non‐significantly reduced in the weight loss groups. ANG‐1 protein levels were significantly reduced 22‐25% after all three interventions (P < 0.01). The ANG‐1/ANG‐2 ratio was also decreased in all three groups (P < 0.05) by 27‐38%. ANGPTL‐4 was increased in the EXO group (15%, P < 0.05) and 9% (P < 0.05) in the DIO group. VEGF‐A, ANG‐1, and ANGPTL‐4 were all expressed in human AT, but only ANGPTL‐4 was influenced by the interventions.

Conclusions:

Our data show that serum VEGF‐A, ANG‐1, ANG‐2, and ANGPTL‐4 levels are influenced by weight changes, indicating the involvement of these factors in the obese state. Moreover, it was found that weight loss generally was associated with a reduced angiogenic activity in the circulation.