Review: The angiogenic and vasodilatory utero-placental network.

The objective of this review is to propose addition of the kallikrein-kinin system (KKS) to the conventional angiogenic repertoire of gestation. This proposal is based on the improved revascularization induced by transfecting the human kallikrein gene; on the angiogenic, chemoattractant, promigratory, antiapoptotic, and antiaggregating effects of bradykinin; and on suppression of these effects by blockade of the bradykinin B2 receptor. In addition, both bradykinin and vascular endothelial growth factor (VEGF) stimulate nitric oxide (NO), and the VEGF and bradykinin receptors have multiple interactions that converge in the endothelial NO synthase (eNOS)-NO pathway. The work of others, and of our group, have demonstrated that eNOS and matrix metalloproteinases, the components of the VEGF and kallikrein-kinin systems, colocalize in specific cell types at human and guinea-pig utero-placental interfaces. Expression of the endothelial angiogenic/vasodilatory repertoire in the syncytiotrophoblast, and in trophoblasts replacing endothelial cells of the spiral arteries, supports the concept that the intervillous space and the transformed uterine arteries represent genuine new vascular structures that should be included in the analysis of pregnancy-induced neovascularization. We believe that the evidence presented provides support for further studies to test the functional significance of the KKS in placental development.