Augmented vasoconstriction is a hallmark of hypertension and is mediated partly by hyperstimulation of G protein couple receptors (GPCRs) and downstream signaling components. Although GPCR blockade is a key component of current anti-hypertensive strategies, whether hypertension is better managed by directly targeting G proteins has not been thoroughly investigated. Here, we tested whether inhibiting G q/11 proteins in vivo and ex vivo using natural cyclic depsipeptide, FR900359 (FR) from the ornamental plant, Ardisia crenata, and YM-254890 (YM) from Chromobacterium sp. QS3666, or it's synthetic analog, WU-07047 (WU), was sufficient to reverse hypertension in mice. All three inhibitors blocked G protein-dependent vasoconstriction, but to our surprise YM and WU and not FR inhibited K +-induced Ca 2+ transients and vasoconstriction of intact vessels. However, each inhibitor blocked whole-cell L-type Ca 2+ channel current in vascular smooth muscle cells. Subcutaneous injection of FR or YM (0.3 mg/kg, s.c.) in normotensive and hypertensive mice elicited bradycardia and marked blood pressure decrease, which was more severe and long lasting after the injection of FR relative to YM (FR t1/2 ≅ 12 hr vs. YM t1/2 ≅ 4 hr). In deoxycorticosterone acetate (DOCA)-salt hypertension mice, chronic injection of FR (0.3 mg/kg, s.c., daily for seven days) reversed hypertension (vehicle SBP: 149 ± 5 vs. FR SBP: 117 ± 7 mmHg), without any effect on heart rate. Our results together support #

Background Decreased uterine blood flow is known to contribute to pregnancy complications such as gestational hypertension and preeclampsia. Previously, we showed that the loss of regulator of G protein signaling 2 ( RGS 2), a GTP ase activating protein for G q/11 and G i/o class G proteins, decreases uterine blood flow in the nonpregnant state in mice. Here, we examined the effects of the absence of RGS 2 and 5 on uterine blood flow and uterine vascular structure and function at early, mid, and late gestation, as well as peripartum period in mice. Methods and Results Abdominal Doppler ultrasonography was performed on adult female wild‐type, Rgs2 −/− , and Rgs5 −/− mice at pre‐pregnancy, gestational days 10, 15, and 18, and postpartum day 3. Uterine artery structure and function were also assessed by vessel myograph studies. At mid‐pregnancy, uterine blood flow decreased in both Rgs2 −/− and Rgs5 −/− mice, whereas resistive index increased only in Rgs2 −/− mice. In uterine arteries from wild‐type mice, mRNA expression of RGS 2 and 4 increased, whereas RGS 5 expression remained elevated at mid‐pregnancy. These changes in gene expression were unique to uterine arteries because they were absent in mesenteric arteries and the aorta of wild‐type mice. In Rgs2 −/− mice, uterine artery medial cross‐sectional area and G protein–coupled receptor‐mediated vasoconstriction increased in mid‐pregnancy, implicating a role for RGS 2 in structural and functional remodeling of uterine arteries during pregnancy. In contrast, RGS 5 absence increased vasoconstriction only in the peripartum period. Conclusions These data together indicate that RGS 2 plays a critical role in the structural and functional remodeling of uterine arteries to impact uterine blood flow during pregnancy. Targeting the signaling pathway regulated by RGS 2 may therefore be a therapeutic strategy for ameliorating utero‐placental perfusion disorders during pregnancy.

IntroductionWhen administered during pregnancy, antibodies and other biologic drugs that contain the Fc part of the IgG molecule can traverse the placenta. Although it is generally accepted that the FcRn receptor mediates this process, gaps remain in our understanding of underlying details in humans and in common laboratory animal species.MethodsWe expanded our previous studies in timed-pregnant guinea pigs to both measure the transport of human (h) IgG at earlier gestation ages in vivo and evaluate FcRn function in vitro using Surface Plasmon Resonance (SPR) and Madin–Darby canine kidney cells (MDCK) that express guinea pig (gp) FcRn.ResultsIn timed-pregnant guinea pigs both the average concentration of hIgG in the fetus and its ratio to maternal hIgG concentration increase exponentially with gestation age. Thus, hIgG fetal:maternal concentration ratios increase from an average of 1% to 3%, 17%, and 76% on GD ~26, 35, 46, and 54, respectively. In vitro, gpFcRn immobilized on a solid surface can bind hIgG and gpIgG preparations in a similar manner. All engineered human Fc isotype-specific constructs were internalized by MDCK-gpFcRn cells at significant levels. While not significant, their recycling and hIgG transcytosis by this cell line also trend higher than background controls.DiscussionPregnant guinea pigs exhibit similarities with humans in the degree and timing of trans-placental transfer as well as the ability of their FcRn to bind and internalize hIgG in vitro. Further studies are needed to guide building appropriate systems for the evaluation of FcRn mediated function of human immunoglobulin therapies.

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Renal dysfunction is a hallmark of spinal cord injury (SCI). Several SCI sequalae are implicated, however, the exact pathogenic mechanism of renal dysfunction is unclear. Herein, we found that T3 (T3Tx) or T10 (T10Tx) complete thoracic spinal cord transection induced hypotension, bradycardia, and hypothermia immediately after injury. T3Tx-induced hypotension but not bradycardia or hypothermia slowly recovered to levels in T10Tx SCI and uninjured mice ~16 h after injury as determined by continuous radiotelemetry monitoring. Both types of thoracic SCI led to a marked decrease in albuminuria and proteinuria in all phases of SCI, while the kidney injury marker, NGAL, rapidly increased in the acute phase, remaining elevated in the chronic phase of T3Tx SCI. Renal interstitial and vascular elastin fragmentation after SCI were worsened during chronic T3Tx SCI. In the chronic phase, renal vascular resistance response to a step increase in renal perfusion pressure or a bolus injection of Ang II or NE was almost completely abolished after T3Tx SCI. Bulk RNAseq analysis showed enrichment of genes involved in extracellular matrix (ECM) remodeling and chemokine signaling in the kidney from T3Tx SCI mice. Serum levels of interleukin 6 was elevated in the acute but not chronic phase of T3Tx and T10Tx SCI, while serum amyloid A1 level was elevated in both acute and chronic phases. We conclude that tissue fibrosis and hemodynamic impairment are involved in renal dysfunction resulting from thoracic SCI; these pathological alterations, exacerbated by high thoracic-level injury, is mediated at least partly by renal microvascular ECM remodeling.