**3. Bridging PlGF and Hypertension**

In recent years, in addition to the known altered mechanisms involved in inducing hypertension (e.g., salt-water balance, cardiovascular function, and peripheral vascular resistance), several clinical and experimental evidences have supported the involvement of the immune system in the occurrence of hypertension [47–49,229–233]. This belief arises from observations on animal models, in which immune cells are crucial players in the onset of hypertension, infiltrating vessel walls and kidneys of hypertensive animals [234,235]. However, only a few studies have provided a mechanistic explanation for how immune cell functions promote blood pressure increases. Severe combined immunodeficiency mice or recombinase-activating gene-1 (*Rag-1*−/−) knockout mice, which lacked both T and B lymphocytes, showed blunted hypertension responses and did not develop abnormalities of vascular function to angiotensin II (ANGII) treatment [236,237]. However, hypertension and vascular dysfunction were restored when *Rag-1*−/<sup>−</sup> mice received adoptive transfer of T cells, but not B cells. Furthermore, after the adoptive transfer of T cells, *Rag-1*−/<sup>−</sup> mice challenged with ANGII significantly increased T cell production of IFN-γ and TNF-α and treatment with a TNF-α antagonist prevented hypertension induced by ANGII, indicating the role of inflammation in inducing hypertension [237]. In addition, IL-10 knockout mice, unable to direct T cells to an anti-inflammatory phenotype, developed symptoms similar to PE when pregnant, confirming the role of T cells in the onset of this syndrome [238]. Conversely, IL-10 treatment reduced inflammation, endothelial dysfunction, and blood pressure in hypertensive pregnant rats [239]. Again, the evidence indicates that production of proinflammatory cytokines, including TNF-α, IL-17, and IL-6, contribute to hypertension, likely by promoting vasoconstriction, production of reactive oxygen species, and sodium reabsorption in the kidney [240,241]. Remarkably, each of these cytokines is reciprocally interconnected with PlGF because, by activating the same transcription factors, they create a self-feeding circuit [34,36]. Overall, these observations support the role of PlGF in the immune system and also the development of PE.

Experimental evidence in pregnant animals indicates that PlGF is a potent arterial vasodilator and may participate in the mechanisms regulating the maternal vascular tone during pregnancy [242]. Therefore, an inadequate level of PlGF during pregnancy may be accountable for the onset of PE [51,59,77,104,243]. A recent study revealed that PlGF had biological effects on samples of uterine arteries, obtained from normotensive women undergoing cesarean hysterectomy, when challenged with ANGII. This study showed that PlGF contributed to the blunted vascular response to ANGII during normotensive pregnancies and sFlt-1/sVEGFR-1 appeared to attenuate this effect contributing to the regulation of vascular tone by altering the vascular response to ANGII [244].

Although the role of PlGF in inducing hypertension during pregnancy has been associated with several mechanisms involving immune cells and cytokines dysregulation, a definitive link between PlGF-induced hypertension and the immune system, even in non-pregnant animal models, was reported in a study by Carnevale et al. The authors demonstrated that PlGF, through mediating a neuroimmune interaction, played a key role in the spleen's immune system by organizing the T-cell response to hypertensive challenge in ANGII-treated mice. Whereas the chronic ANGII infusion produced a progressive increase in blood pressure in wild-type (wt) mice, due to an accumulation of T lymphocytes in the aortic wall and kidney, the hypertensive response was completely abolished in *plgf*−/<sup>−</sup> mice. Mechanistically, PlGF mediated the hypertension response to ANGII challenge by repressing tissue inhibitor of metalloproteinases (Timp)-3 protein expression in macrophages, through the transcriptional Sirtuin (Sirt)1-p53 axis. In turn, Timp3 repression allowed the costimulation of T cells and their deployment toward classical organs involved in hypertension [245]. Overall, these data are definitive evidence of the link between PlGF and hypertension through immune-mediated mechanisms.
