Our data suggest that plasma PK, activated on the surface of exposed VSMC, may be one such factor, not only generating BK but causing direct PAR1/2 activation, EGF receptor transactivation, and KPT-330 CRM1 the release of proinflammatory cytokines. As such, KK, which also increases RAS activity by activating prorenin, may be an attractive therapeutic target for the treatment of vascular disease in high risk settings. *This work was supported, in whole or in part, by National Institutes of Health Grants HL087986 and HL077192 (to A. A. J.), and DK55524 (to L. M. L.). This work was also supported by the South Carolina Center for Biomedical Research Excellence in Cardiovascular Diseases (to D. K. L.) and Department of Veterans Affairs Research Enhancement Award Program awards.
2The abbreviations used are: KKS kallikrein-kinin system AR amphiregulin BK bradykinin EAA1 early endosomal antigen 1 VSMC vascular smooth muscle cell R-VSMC rat aortic VSMC H-VSMC human aortic VSMC HB heparin-binding HMWK high molecular weight kininogen KK kallikrein MMP matrix metalloprotease PAR protease-activated receptor PK prekallikrein RAS renin-angiotensin system TACE TNF-�� converting enzyme.
Understanding how Plasmodium-Anopheles interactions contribute to the mosquito vector competence has received great attention lately, and the increasing knowledge promises to contribute to the development of new malaria control strategies �C. Malaria still remains a serious health problem in developing African countries, causing more than 1 million deaths annually.
Almost all these deaths are caused by the parasite Plasmodium falciparum whose major vector in Africa is Anopheles gambiae, which is widely distributed throughout the afro-tropical belt. A. gambiae s.s. is divided into two morphologically indistinguishable molecular forms, known as M and S, which are regarded as incipient species �C. The M and S molecular forms exhibit ecological preferences , , but their respective epidemiological importance in malaria transmission has been poorly documented so far , . The susceptibility of Anopheles mosquitoes to Plasmodium infection is under genetic control �C, but the large variability in oocyst number among closely related mosquitoes indicates that environmental factors also play a role. Multiple lines of evidence suggest that mosquito bacterial communities influence vector competence �C.
A protective role of Anopheles midgut bacteria against malaria infections was demonstrated by using antibiotic treatment to clear the gut microbiota, AV-951 which resulted in enhanced Plasmodium infections , . Consistently, coinfections of bacteria with Plasmodium reduced the number of developing oocysts in the mosquito midgut, both in laboratory and field conditions , , �C. Interestingly, Cirimotich et al.