The nuclear translocation was demonstrated by markedly increased PLZF in cardiocyte nuclei of Ang II-infused wild type mice and also in AT2-expressing R3T3 cells transfected with a PLZF-expression plasmid. It is this AT2-mediated nuclear translocation of PLZF that accounts for the activation of p85a in the previous studies and GATA4 in the present study. The activation of the PI3K/Akt signal leads to cellular hypertrophy due to stimulation of protein synthesis by p70S6k. Moreover, GSK3? is another important downstream hypertrophic factor in the PI3K/Akt signal pathway. GSK3? phosphorylates GATA4 to promote its export from the nucleus through the exportin, Crm1. Akt inhibits GSK3? activity and enhances nuclear accumulation of GATA4. Taken together the Ang II-AT2 exerted multiple convergent effects directed to cardiac hypertrophy through activation of p85a PI3K and p70S6k, inhibition of GSK3? to facilitate nuclear localization of GATA4 and stimulation of GATA4 transcription. Cardiac AT2 is up-regulated by mechanical stretch and pressure overload. Moreover, AT2 promotes ligandindependent, constitutive cardiomyocyte hypertrophy. AT1 and AT2 receptors are considered to interact with each other to enhance the effects they mediate. Combined treatment with losartan and PD123319 proved to be more effective in attenuating the reflex increase in plasma adrenaline concentrations during insulin-induced hypoglycemia than either of the two Ang II GBR-12935 receptor antagonists given alone. Furthermore, the combination of both AT1 and AT2 receptor antagonists, at concentrations that each partly reduced inositol 1,4,5-trisphosphate, completely inhibited IP3 formation, suggesting that AT1 and AT2 cooperate in Ang II-mediated IP3 signal transduction for the actions of Ang II mediated by the IP3 signal transduction pathway. Because GATA4 with AP-1 up-regulates AT1 receptor expression, our study provides insight into a plausible mechanism of interaction between AT1 and AT2 signaling pathways, in which PLZF bridges AT2 and AT1 signaling through GATA4. Thus, AT2 could be an upstream cardiac hypertrophy factor of AT1 signaling. The interactions between AT1 and AT2 are complicated but the comprehensive understanding of these mechanisms could lead to better understanding of the therapeutic strategies of hypertension and cardiac hypertrophy. Thus, while parenchymal damage is considered to be the initial event in PH pathogenesis, its impact on the hepatic microvasculature appears to be the proximal cause of PH and its sequela. Here we examined whether enforced sinusoidal capillarization, not accompanied by parenchymal architectural derangement may lead to PH. To this end, we have developed a unique transgenic mouse model for perturbing the hepatic vasculature in a conditional and reversible manner via manipulations of Vascular Endothelial Growth Factor. VEGF, in addition to its activity as an angiogenic factor, also thought to play multiple roles in adult vasculatures. Notably, VEGF was shown to induce endothelial fenestration in vitro. Likewise, VEGF blockade during Soyasaponin-Bb development resulted in generation of sinusoidal endothelial cells with fewer fenestrations. Other studies have shown that fenestrated endothelium, in general, is more vulnerable to VEGF withdrawal than non-fenestrated endothelium. The notion that ongoing VEGF signaling might be required to maintain fenestrations in adult SECs in vivo, however, has not been examined.