Regulator of G Protein Signaling 2 Facilitates Uterine Artery Adaptation During Pregnancy in Mice.

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 Gq/11 and Gi/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.

p21-Activated kinase 1 is required for efficient tumor formation and progression in a Ras-mediated skin cancer model.

The RAS genes are the most commonly mutated oncogenes in human cancer and present a particular therapeutic dilemma, as direct targeting of Ras proteins by small molecules has proved difficult. Signaling pathways downstream of Ras, in particular Raf/Mek/Erk and PI3K/Akt/mTOR, are dominated by lipid and protein kinases that provide attractive alternate targets in Ras-driven tumors. As p21-activated kinase 1 (Pak1) has been shown to regulate both these signaling pathways and is itself upregulated in many human cancers, we assessed the role of Pak1 in Ras-driven skin cancer. In human squamous cell carcinoma (SCC), we found a strong positive correlation between advanced stage and grade and PAK1 expression. Using a mouse model of Kras-driven SCC, we showed that deletion of the mouse Pak1 gene led to markedly decreased tumorigenesis and progression, accompanied by near total loss of Erk and Akt activity. Treatment of Kras(G12D) mice with either of two distinct small molecule Pak inhibitors (PF3758309 and FRAX597) caused tumor regression and loss of Erk and Akt activity. Tumor regression was also seen in mice treated with a specific Mek inhibitor, but not with an Akt inhibitor. These findings establish Pak1 as a new target in KRAS-driven tumors and suggest a mechanism of action through the Erk, but not the Akt, signaling pathway.