Administration of recombinant human placental growth factor decreases blood pressure in obese hypertensive pregnant rats.

OBJECTIVES: Although epidemiological studies have shown that obesity is associated with increased incidence of hypertension during pregnancy, the mechanisms linking these two comorbidities are not as well studied. Previous investigations detected lower levels of the anti-hypertensive and pregnancy-related factor, placental growth factor (PlGF), in obese hypertensive pregnancies. Therefore, we examined whether obese hypertensive pregnant rats have reduced PlGF and whether increasing its levels by administering recombinant human (rh)PlGF reduces their blood pressure. METHODS: We utilized a genetic model of obesity characterized to be heavier, hypertensive and fertile, namely rats having heterozygous deficiency of the melanocortin-4 receptor (MC4R-def). RESULTS: MC4R-def obese rats had lower circulating levels of PlGF than wild-type lean controls at gestational day 19. Also, assessment of the PlGF receptor, Flt-1, in the vasculature showed that its levels were reduced in aorta and kidney glomeruli but increased in small mesenteric arteries. Chronic intraperitoneal administration of rhPlGF from gestational day 13-19 significantly increased circulating PlGF levels in both obese and lean rats, but reduced blood pressure only in the obese pregnant group. The rhPlGF treatment did not alter maternal body and fat masses or circulating levels of the adipokines, leptin and adiponectin. In addition, this treatment did not impact average foetal weights but increased placental weights regardless of obese or lean pregnancy. CONCLUSION: PlGF is reduced in MC4R-def obese hypertensive pregnant rats, which is similar to findings in obese hypertensive pregnant women, while increasing its levels with exogenous rhPlGF reduces their blood pressure.

The placental growth factor attenuates intimal hyperplasia in vein grafts by improving endothelial dysfunction.

Saphenous vein grafts (SVG) patency is limited by intimal hyperplasia (IH) caused by endothelial dysfunction. This study aimed to explore the effect of placental growth factor (PlGF) on the endothelial function of SVG. In rat models of external jugular vein-carotid artery graft treated with PlGF or saline hydrogel, PlGF inhibited vein graft IH (day 28: 12.0 ± 1.9 vs. 61.7 ± 13.1 µm, P < 0.001), promoted microvessel proliferation (day 14: 33.3% 3+ vs. 50.0% 2+, P = 0.03), and increased nitric oxide (NO) production (P < 0.05 on days 1/3/5) and NO synthase (NOS) expression by immunohistochemistry. In human umbilical vein endothelial cells (HUVECs) cultured under hypoxia and treated or not with PlGF, PlGF restored the survival (50 ng/ml PlGF, 48 h: 91.7 ± 0.6% vs. 84.9 ± 0.5%, P < 0.01), migration (by Matrigel assay), and tube formation ability (junctions, tubules, and tubule total length; all P < 0.01) of HUVECs after hypoxia. PlGF increased NO production through increased eNOS expression (P < 0.05), without changes in iNOS expression. The mRNA expression of eNOS decreased after the addition of the PI3K inhibitor LY294002 (P < 0.05). PlGF promoted the protein expression of eNOS by up-regulating AKT, and the AKT and eNOS protein levels were decreased after adding LY294002 (all P < 0.05). In conclusion, PlGF is a candidate for the inhibition of IH in SVG after coronary artery bypass graft. The effects of PlGF are mediated by the upregulation of the eNOS mRNA and protein through the PI3K/AKT signaling pathway. PlGF promotes the secretion of NO by endothelial cells and thereby reduces the occurrence and development of IH.

Treatment with placental growth factor attenuates myocardial ischemia/reperfusion injury.

Studies have established that oxidative stress plays an important role in the pathology of myocardial ischemia/reperfusion injury (MIRI). Vascular endothelial growth factor receptor 1 (VEGFR1) activation was reported to reduce oxidative stress and apoptosis. In the present study, we tested the hypothesis that the activation of VEGFR1 by placental growth factor (PlGF) could reduce MIRI by regulating oxidative stress. Mouse hearts and neonatal mouse cardiomyocytes were subjected to ischemia/reperfusion (I/R) and oxygen glucose deprivation (OGD), respectively. PlGF pretreatment markedly ameliorated I/R injury, as demonstrated by reduced infarct size and improved cardiac function. The protection was associated with a reduction of cardiomyocyte apoptosis. Similarly, our in vitro study showed that PlGF treatment improved cell viability and reduced cardiomyocyte apoptosis. Also, activation of VEGFR1 by PlGF suppressed intracellular and mitochondrial reactive oxygen species (ROS) generation. However, VEGFR1 neutralizing monoclonal antibody, which preventing PlGF binding, totally blocked this protective effect. In conclusion, activation of VEGFR1 could protect heart from I/R injury by suppression of oxidative stress and apoptosis.

Sustained Placental Growth Factor-2 Treatment Does Not Aggravate Advanced Atherosclerosis in Ischemic Cardiomyopathy.

Angiogenic growth factor therapy for ischemic cardiovascular disease carries a risk of stimulating atherosclerotic plaque growth. We evaluated risk benefit ratio of sustained administration of recombinant human placental growth factor (rhPlGF)-2 in mice with advanced atherosclerosis and chronic ischemic cardiomyopathy. We maintained apolipoprotein E-deficient mice on a high cholesterol diet and induced myocardial infarction by transient ligation at 4 weeks. At 8 weeks, we assessed left ventricular (LV) function and randomized mice to receive rhPlGF-2 or vehicle (VEH) subcutaneously for 28 days. Administration of rhPlGF-2 significantly increased PlGF plasma levels without adverse hemodynamic or systemic inflammatory effects. RhPlGF-2 did not increase plaque area, composition, or vulnerability in the aortic arch. RhPlGF-2 significantly improved contractile function and reduced LV end-systolic and end-diastolic volume indices with a concomitant increase in capillary and arteriolar density in ischemic myocardium. RhPlGF-2 may represent a promising therapeutic strategy in chronic ischemic cardiomyopathy.

[Placenta Growth Factor (PlGF) and Retinal Vascular Diseases--Current Knowledge from Experimental and Clinical Studies]. / Plazenta-Wachstumsfaktor (PlGF) und retinale Gefäßerkrankungen--experimentelle und klinische Datenlage.

Pathological angiogenesis is a major characteristic of many diseases, such as cancer and retinal vascular disorders. Vascular diseases of the eye, such as diabetic retinopathy (DR) and neo-vascular age-related macular degeneration (nAMD), are the main cause of severe vision loss. The specific role of the cytokine VEGF-A in these pathologies has been proven in many ways. Thus, VEGF-A is still the major target for antiangiogenic therapy. Recently, another angiogenic factor, the placental growth factor (PlGF), has become a focal point for clinical research. This interest is based on the fact that the expression of PlGF is limited to embryonic development and PlGF can hardly be found in healthy tissues. During pathological angiogenetic processes, such as retinal vascular diseases, however, PlGF is increasingly expressed. Substances which inhibit the effect of PlGF and thus pathological angiogenesis, without simultaneously affecting healthy tissues, could significantly extend the therapeutic options for the treatment of retinal vascular diseases. Convincing results have recently been published from clinical trials in oncology, as well as preclinical investigations in animal models of retinal vascular diseases. The aim of this review is to summarise the role of PlGF in retinal vascular diseases and the available experimental data on the therapeutic potential of PlGF inhibitors.