Diabetes is a common comorbidity in stroke patients and a strong predictor of poor functional outcome. To provide a more mechanistic understanding of this clinically relevant problem, we focused on how diabetes affects blood-brain barrier (BBB) function after stroke. Because the BBB can be compromised for days after stroke and thus further exacerbate ischemic injury, manipulating its function presents a unique opportunity for enhancing stroke recovery long after the window for thrombolytics has passed. Using a mouse model of Type 1 diabetes, we discovered that ischemic stroke leads to an abnormal and persistent increase in vascular endothelial growth factor receptor 2 (VEGF-R2) expression in peri-infarct vascular networks. Correlating with this, BBB permeability was markedly increased in diabetic mice, which could not be prevented with insulin treatment after stroke. Imaging of capillary ultrastructure revealed that BBB permeability was associated with an increase in endothelial transcytosis rather than a loss of tight junctions. Pharmacological inhibition (initiated 2.5 d after stroke) or vascular-specific knockdown of VEGF-R2 after stroke attenuated BBB permeability, loss of synaptic structure in peri-infarct regions, and improved recovery of forepaw function. However, the beneficial effects of VEGF-R2 inhibition on stroke recovery were restricted to diabetic mice and appeared to worsen BBB permeability in nondiabetic mice. Collectively, these results suggest that aberrant VEGF signaling and BBB dysfunction after stroke plays a crucial role in limiting functional recovery in an experimental model of diabetes. Furthermore, our data highlight the need to develop more personalized stroke treatments for a heterogeneous clinical population.
In Experiment 1, 308 Holstein cows were assigned randomly to four treatments: 1) GnRH injection followed in 7 d by PGF2 alpha injection, then another GnRH injection 33 h later, and artificial insemination (AI) 16 to 18 h after the second GnRH injection; 2) GnRH injection followed in 7 d by PGF2 alpha injection and AI only after detected estrus; 3) injections of PGF2 alpha 14 d apart, GnRH injection 33 h after the second PGF2 alpha injection, and AI 16 to 18 h later; and 4) injections of PGF2 alpha 14 d apart, AI only after detected estrus following the second PGF2 alpha injection or, in the absence of detected estrus, at 80 h after the second PGF2 alpha injection. In Experiment 2, 227 Holstein cows were assigned randomly to two treatments: 1) GnRH injection followed in 7 d by PGF2 alpha injection, then another GnRH injection 48 h later, and AI 16 to 18 h after the second GnRH injection; and 2) GnRH injection followed in 7 d by PGF2 alpha injection and AI only after detected estrus. Although conception rates in both experiments resulting from AI made after detected estrus either tended to be greater or were consistently greater than those following GnRH injection and one fixed-time AI, pregnancy rates were of greater magnitude after fixed-time AI because of poor expression or detection of estrus.
Three experiments were conducted to induce estrus and(or) ovulation in 1,590 suckled beef cows at the beginning of a spring breeding season. In Exp. 1, 890 cows at three locations were allotted to three treatments: 1) GnRH on d -7 + prostaglandin F2alpha (PGF2alpha) on d 0 (Select Synch); 2) GnRH on d -7 + PGF2alpha on d 0 (first day of the breeding season) plus a norgestomet implant (NORG) between d -7 and 0 (Select Synch + NORG); or 3) two injections of PGF2alpha given 14 d apart (2xPGF2alpha). More (P < 0.05) cycling cows were detected to have been in estrus after both treatments that included GnRH, whereas, among noncycling cows, the addition of norgestomet further increased (P < 0.05) the proportion in estrus. Pregnancy rates were greater (P < 0.01) among noncycling cows after treatments that included GnRH. For cows that calved >60 d before the onset of the breeding season, conception rates were greater (P < 0.01) than those that calved < or =60 d regardless of treatment, whereas days postpartum had no effect on rates of detected estrus. When body condition scores were < or =4 compared with >4, rates of detected estrus (P < 0.05) and conception (P = 0.07) were increased. In Exp. 2, 164 cows were treated with the Select Synch + NORG treatment and were inseminated either after estrus or at 16 h after a second GnRH injection (given 48 h after PGF2alpha). Conception and pregnancy rates tended (P = 0.08) to be or were less (P < 0.05), respectively, for noncycling cows inseminated by appointment, but pregnancy rates exceeded 53% in both protocols. In Exp. 3, 536 cows at three locations were treated with the Select Synch protocol as in Exp. 1 and inseminated either: 1) after detected estrus (Select Synch); 2) at 54 h after PGF2alpha when a second GnRH injection also was administered (Cosynch); or 3) after detected estrus until 54 h, or in the absence of estrus, at 54 h plus a second GnRH injection (Select Synch + Cosynch). Conception rates were reduced (P < 0.01) in cows that were inseminated by appointment. An interaction of AI protocol and cycling status occurred (P = 0.05) for pregnancy rates with differing results for cycling and noncycling cows. Across experiments, variable proportions of cows at various locations (21 to 78%) were cycling before the breeding season. With the GnRH or GnRH + NORG treatments, ovulation was induced in some noncycling cows. Conception rates were normal and pregnancy rates were greater than those after a PGF2alpha program, particularly when inseminations occurred after detected estrus.
Cycling (n = 16) and noncycling (n = 24), early postpartum, suckled beef cows of three breeds were assigned randomly to three treatments: 1) 100-microg injection of GnRH plus a 6-mg implant of norgestomet administered on d -7 before 25 mg of PGF2alpha and implant removal on d 0 (GnRH+NORG); 2) 100 microg of GnRH given on d -7 followed by 25 mg of PGF2alpha on d 0 (GnRH); or 3) 2 mL of saline plus a 6-mg implant of norgestomet administered on d -7 followed by 25 mg of PGF2, and implant removal on d 0 (NORG). All cows were given 100 microg of GnRH on d +2 (48 h after PGF2alpha). Blood sera collected daily from d -7 to d +4 were analyzed for progesterone and estradiol-17beta, and ovaries were monitored daily by transrectal ultrasonography to assess changes in ovarian structures. Luteal structures were induced in 75% of noncycling cows in both treatments after GnRH, resulting in elevated (P < .01) progesterone on d 0 for GnRH+NORG-treated cows. Concentrations of estradiol-17beta (P < .01) and LH (P < .05) were greater on d +2 after GnRH for cows previously receiving norgestomet implants. Pregnancy rates after one fixed-time AI at 16 h after GnRH (d +2) were greater (P < .05) in GnRH+NORG (71%) than in GnRH (31%) and NORG (15%) cows. Difference in pregnancy rate was due partly to normal luteal activity after AI in over 87% of GnRH+NORG cows and no incidence of short luteal phases. The GnRH+NORG treatment initially induced ovulation or turnover of the largest follicle, induction of a new follicular wave, followed later by increased concentrations of estradiol-17beta and progesterone. After PGF2alpha, greater GnRH-induced release of LH occurred in GnRH+NORG cows before ovulation, and pregnancy rates were greater after a fixed-time AI.
Two experiments were conducted to determine whether milking beef cows two or five times daily in the presence or absence of their own nonsuckling calves would alter postpartum interval to first ovulation. Multiparous Angus x Hereford cow-calf pairs were assigned randomly between 13 and 18 d postpartum to treatments for 4 wk. In Exp. 1, pairs were assigned to six treatments: 1) calf was weaned permanently from its dam (CW; n = 9); 2) same as CW, but dam was milked twice daily (CW+2xM; n = 9); 3) calf was present continuously with its dam but restricted from contact with the udder (CR; n = 9); 4) same as CR, but dam was milked twice daily (CR+2xM; n = 9); 5) same as CR, but calf was allowed to suckle twice daily (CR+2xS; n = 8); and 6) calf was present continuously with its dam and suckled ad libitum (CP; n = 9). The interval from onset of treatments to first postpartum ovulation was shorter (P<.05) in the CW (14.1+/-3.1 d), CR (14.2+/-3.1 d), CW+2xM (13.0+/-3.1 d), and CR+2xM (17.2+/-3.1 d) than in the CP (34.7+/-3.1 d) and CR+2xS (33.9+/-3.3 d) treatments. Daily milk yield during treatment was greater (P<.01) for CR+2xM cows (7.1+/-.6 kg) than for CW+2xM cows (3.5+/-.6 kg). In Exp. 2, cow-calf pairs were assigned to three treatments: 1) CR+2xM (n = 10); 2) same as CR+2xM but cows were milked five times daily (CR+5xM; n = 10); or 3) CP (n = 10). The interval to first postpartum ovulation was shorter (P<.05) in the CR+2xM (23.6+/-3.5 d) and CR+5xM (26.1+/-3.7 d) treatments than in the CP (37.7+/-3.7 d) treatment. Daily milk yield during treatment was greater (P<.05) for CR+5xM cows (7.7+/-.6 kg) than for CR+2xM cows (6.4+/-.6 kg) by 17%. We conclude that suckling twice daily was sufficient to prolong postpartum anestrus as much as suckling ad libitum. Furthermore, milk removal by suckling, but not by milking two or five times daily, even in the presence of the cow's own nonsuckling calf, is essential to prolong postpartum anovulation.
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