Prohypertensive Factors Research Articles

Bioflavonoid luteolin prevents sFlt-1 release via HIF-1α inhibition in cultured human placenta.

Preeclampsia (PE) is a serious hypertensive complication of pregnancy and is a leading cause of maternal death and major contributor to maternal and perinatal morbidity, including establishment of long-term complications. The continued prevalence of PE stresses the need for identification of novel treatments which can target prohypertensive factors implicated in the disease pathophysiology, such as soluble fms-like tyrosine kinase 1 (sFlt-1). We set out to identify novel compounds to reduce placental sFlt-1 and determine whether this occurs via hypoxia-inducible factor (HIF)-1α inhibition. We utilized a commercially available library of natural compounds to assess their ability to reduce sFlt-1 release from primary human placental cytotrophoblast cells (CTBs). Human placental explants from normotensive (NT) and preeclamptic (PE) pregnancies were treated with varying concentrations of luteolin. Protein and mRNA expression of sFlt-1 and upstream mediators were evaluated using ELISA, western blot, and real-time PCR. Of the natural compounds examined, luteolin showed the most potent inhibition of sFlt-1 release, with >95% reduction compared to vehicle-treated. Luteolin significantly inhibited sFlt-1 in cultured placental explants compared to vehicle-treated in a dose- and time-dependent manner. Additionally, significant decreases in HIF-1α expression were observed in luteolin-treated explants, suggesting a mechanism for sFlt-1 downregulation. The ability of luteolin to inhibit HIF-1α may be mediated through the Akt pathway, as inhibitors to Akt and its upstream regulator phosphatidylinositol-3 kinase (PI3K) resulted in significant HIF-1α reduction. Luteolin reduces anti-angiogenic sFlt-1 through inhibition of HIF-1α, making it a novel candidate for the treatment of PE.

S-07-7: ANGIOTENSIN, VASCULAR AGING AND HYPERTENSION

Aging is a major non-modifiable risk factor underlying hypertension and associated cardiovascular disease. With aging, the vasculature undergoes structural, functional and mechanical alterations characterized by endothelial dysfunction, media thickening, reduced distensibility, and arterial stiffening. Many of these processes are associated with activation of the renin angiotensin aldosterone system (RAAS), which is characteristically associated with the pathophysiology of hypertension. In particular Ang II, through the AT1 receptor, and aldosterone through the mineralocorticoid receptor, activate pro-inflammatory and pro-fibrotic signaling pathways that lead to vascular fibrosis, extracellular matrix (ECM) deposition, arterial remodelling, perivascular inflammation and hyperreactivity. These processes are also associated with aging and are amplified by hypertension. Molecular mechanisms underlying these events include increased expression and activation of matrix metalloproteinases, activation of transforming growth factor1/SMAD signalling, upregulation of galectin-3, activation of aging signaling pathways, eg p66Shc, c-Src, and oxidative stress. Fundamental to these processes is phenotypic switching of vascular smooth muscle cells from a contractile to de-differentiated state. This involves epigenetic changes and alterations in the vascular proteome. Complex interplay between the “aging process” and prohypertensive factors, including Ang II and aldosterone, result in accelerated vascular remodelling and fibrosis and increased arterial stiffness, which is typically observed in hypertension. Because the vascular phenotype in a young hypertensive individual resembles that of an elderly otherwise healthy individual, the notion of “early” or “premature” vascular aging is frequently used to describe hypertension-associated vascular disease. This presentation discusses the vascular phenotype in aging and hypertension and the role of the RAAS. In addition novel molecular mechanisms, focusing on oxidative stress and the vascular proteome will be highlighted.

Voluntary Exercise Eliminates Maternal Gestational Hypertension-Induced Hypertensive Response Sensitization to Postweaning High-Fat Diet in Male Adult Offspring.

Exercise has profound effects on cardiovascular function and metabolism in both physiological and pathophysiological states. The present study tested whether voluntary exercise would protect male offspring against maternal gestational hypertension-induced hypertensive response sensitization elicited by post-weaning high-fat diet (HFD). On low-lard-fat diet, offspring of both normotensive and hypertensive dams had comparable resting blood pressure, but HFD feeding elicited an enhanced increase in blood pressure (ie, hypertensive response sensitization) in sedentary offspring of hypertensive dams when compared with sedentary offspring of normotensive dams. The HFD fed sedentary offspring of hypertensive dams displayed greater sympathetic activity, enhanced pressor responses to centrally administered ANG II (angiotensin II) or leptin, and greater mRNA expression of proinflammatory cytokines, leptin, and a marker of blood-brain barrier leakage in the hypothalamic paraventricular nucleus. The enhanced blood pressure and central sympathetic activity in HFD-fed sedentary offspring of hypertensive dams were significantly reduced by exercise but fell only to levels comparable to HFD-fed exercising offspring of normotensive dams. HFD-induced increases in plasma IL-6 (interleukin-6) and sympathetic activity and greater pressor responses to central TNF (tumor necrosis factor)-α in offspring from both normotensive and hypertensive dams were also maintained after exercise. Nevertheless, exercise had remarkably beneficial effects on metabolic and autonomic function, brain reactivity to ANG II and leptin and gene expression of brain prohypertensive factors in all offspring. Voluntary exercise plays a beneficial role in preventing maternal hypertension-induced hypertensive response sensitization, and that this is associated with attenuation of enhanced brain reactivity and centrally driven sympathetic activity.

Circulating Total Cell-Free DNA Levels Are Increased in Hypertensive Disorders of Pregnancy and Associated with Prohypertensive Factors and Adverse Clinical Outcomes.

Previous studies have described increased circulating cell-free DNA (cfDNA) in hypertensive disorders of pregnancy (HDP). Here, we aimed first to confirm this information using a simple, but sensible fluorescent assay, and second to investigate whether total cfDNA is associated with circulating factors known to be linked to the pathophysiology of HDP as well as with poor maternal-fetal outcomes. We studied 98 women with healthy pregnancies (HP), 88 with gestational hypertension (GH), and 91 with preeclampsia (PE). Total DNA was extracted from plasma using the QIAamp DNA blood mini kit and quantified using Quant-iT™ PicoGreen® dsDNA fluorescent detection kit. We found higher total cfDNA levels in GH and PE (197.0 and 174.2 ng/mL, respectively) than in HP (140.5 ng/mL; both p < 0.0001). Interestingly, total cfDNA levels were elevated in both male and female-bearing pregnancies diagnosed with either HDP, and in more severe versus less severe HDP cases, as classified according to responsiveness to antihypertensive therapy. In addition, total cfDNA was independently associated with HDP, and a cutoff concentration of 160 ng/mL provided appropriate sensitivity and specificity values for diagnosing GH and PE compared to HP (70–85%, both p < 0.0001). Moreover, high total cfDNA was associated with adverse clinical outcomes (high blood pressure, low platelet count, preterm delivery, fetal growth restriction) and high prohypertensive factors (sFLT-1, sEndoglin, MMP-2). These findings represent a step towards to the establishment of cfDNA as a diagnostic tool and the need to understand its role in HDP.

Vascular age in patients with arterial hypertension

Ageing is considered to be the major and non-modifiable risk factor for the development of hypertension and cardiovascular diseases. During ageing, the vascular system undergoes structural and functional alterations, including endothelial dysfunction, thickening of the vascular wall, reduced distensibility and increased arterial stiffness. Vascular rigidity results from fibrosis and remodelling of the extracellular matrix, processes that are associated with ageing and are amplified in hypertension. These events may be induced by vasoactive agents, such as angiotensin II, endothelin-1, and aldosterone, which are increased in the vasculature during aging and hypertension. Complex interaction between the process of ageing and prohypertensive factors results in accelerated vascular remodelling and fibrosis, as well as increased arterial stiffness. Hypertension accelerates and augments age-related vascular remodelling and dysfunction, and ageing may impact on the severity of vascular damage in hypertension, thus strongly suggesting close interactions between biological ageing and blood pressure elevation. Molecular and cellular mechanisms underlying vascular alterations in ageing and hypertension are common and include aberrant signal transduction, oxidative stress and activation of pro-inflammatory and pro-fibrotic transcription factors. Strategies to suppress age-associated vascular changes can ameliorate vascular damage associated with hypertension. This article looks into vascular alterations occurring during ageing and hypertension, focussing particularly on arterial stiffness and vascular remodelling, also emphasizing the importance of diagnostic methods.

Adrenergic receptor blockade attenuates placental ischemia-induced hypertension.

Preeclampsia (PE), a disorder of new‐onset maternal hypertension and vascular dysfunction during pregnancy, is thought to be linked to placental ischemia‐induced release of prohypertensive factors and reductions of vasoprotective factors in the maternal circulation. Although markers of sympathetic nervous activity are elevated in experimental models of placental ischemia‐induced hypertension and women with PE compared with their normal pregnant counterparts, the importance of adrenergic receptor signaling in the development of hypertension in PE is unknown. Therefore, we tested the hypothesis that adrenergic receptor blockade attenuates the development of placental ischemia‐induced hypertension in rats. Wistar Hannover rats underwent reduced uterine perfusion pressure (RUPP) or Sham surgeries on gestational day 14. By day 19, mean arterial blood pressure (MAP) was increased in RUPP over Sham rats. Groups of RUPP and Sham pregnant rats received terazosin and propranolol (3 mg/kg per day of each via subcutaneous osmotic minipump) to block α 1‐ and β‐adrenergic receptors, respectively, beginning on gestational day 14. Adrenergic blockade significantly attenuated the development of hypertension in the RUPP rats with a slight blood pressure‐lowering response in the Sham, normal pregnant rats by day 19. In conclusion, these data implicate that placental ischemia‐induced hypertension involves adrenergic receptor signaling to promote increases in blood pressure during PE.

Placental Ischemia‐Induced Hypertension Is Abolished by Adrenergic Receptor Blockade

Hypertensive disorders of pregnancy are the number one cause of pregnancy‐related deaths in the United States. Preeclampsia is a disorder of maternal hypertension and vascular dysfunction presenting in the second half of pregnancy along with fetal growth restriction. Currently, there are no steadfast therapies besides early delivery of the fetus and ischemic placenta, which releases pro‐hypertensive factors into the maternal circulation. The sympathetic nervous system might be a novel target in treating preeclampsia, as sympathetic nervous activity is found to be increased in preeclamptic vs. normal pregnant women. However, it is unknown if the sympathetic nervous system mediates the development of placental ischemia‐induced hypertension. In this study, the hypothesis was tested that adrenergic receptor blockade prevents placental ischemia‐induced hypertension. Wistar Hannover rats were randomized to receive reduced uterine perfusion pressure (RUPP, N=15) or Sham RUPP (N=20) surgeries on gestational day 14 and examined at day 19. In RUPP vs. Sham rats, respectively, mean arterial blood pressure (MAP) was increased (121 ± 3 vs. 102 ± 1 mmHg, P&lt;0.05) without a change in heart rate (421 ± 7 vs. 423 ± 4 bpm). Average fetal weights (1.87 ± 0.04 vs. 2.11 ± 0.03 g) and placental weights (0.50 ± 0.02 vs. 0.57 ± 0.01 g) were lower (P&lt;0.05) in RUPP dams. In RUPP over Sham rats, vasoconstriction induced by the alpha‐adrenergic receptor agonist, phenylephrine, was greater in isolated renal interlobar arteries (Emax: 322 ± 19 vs. 251 ± 12 % of KCl response). The Emax response to KCl was not different between RUPP or Sham rats, in sequence: 100 ± 24 vs. 87 ± 14 % increase in force. A subset of RUPP (N=9) and Sham (N=9) rats received combined terazosin and propranolol (3 mg/kg per day of each, subcutaneous osmotic minipump) to block alpha‐ and beta‐adrenergic receptors, respectively, beginning the day of surgery on gestational day 14. By day 19, adrenergic blockade abolished the development of hypertension in RUPP rats (105 ± 2 mmHg, P&lt;0.05) and reduced their heart rate (343 ± 21 bpm, P&lt;0.05) with a lesser reduction detected in treated Sham rats for MAP (97 ± 2 mmHg, P&lt;0.05) and heart rate (387 ± 9 bpm, P&lt;0.05). Treatment did not alter average fetal weights (1.89 ± 0.05 and 2.11 ± 0.03 g) or placental weights (0.47 ± 0.02 and 0.50 ± 0.03 g) in RUPP and Sham rats, in turn, compared to their untreated counterparts. In conclusion, placental ischemia‐induced hypertension depends on activation of the sympathetic nervous system. The mechanisms responsible for this enhanced sympathetic nerve activity and adrenergic receptor signaling remain unknown but are likely to involve factors released from the ischemic placenta.Support or Funding Information4R00HL130577‐02This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Profile of vascular age and vascular response among elderly patients receiving antihypertensive therapy

Background: Normally the age of the arteries is same as that of the chronological age of the patient. In Hypertensive patients, complex interactions occur between prohypertensive factors, accelerating vascular age. Furthermore, prohypertensive factors to some extent are responsible for non-response to therapy at optimal doses. We assessed the correlation between response to therapy and vascular age in elderly hypertensives, in addition to vascular age and vascular response.Methods: In this study, we analysed the clinical records of both male and female hypertensive patients above 60 years old. We collected the details of age, gender, body mass index, systolic blood pressure (treated and untreated), diabetes and smoking. Vascular age was calculated using a composite score of these six prohypertensive risk factors. Accelerated vascular age was then derived using the formula vascular age minus chronological age. The optimal vascular response was considered if the patient's therapeutic blood pressures are less than 140/ 90mmHg.Results: In the present study, data from 517 elderly hypertensive patients were analysed, the mean chronological age, vascular age and accelerated vascular age was 66.74±6.6, 79.46±0.42 and 13.46±6.08 years. Only 32.7% were responders to anti-hypertensive treatment. The pattern of usage of anti-hypertensives in our patients is CCBs 39.10% followed by 30.90% ARB, 22.50% ACEI and 8.90% diuretics. The response in 20.50% of patients was achieved with a single drug, in 9.90% with two drugs and only in 2.30% of patients using three drugs. We found that 78.72% of our study population had vascular age more than ten years of chronological age, among them 66.6% between 60-69 years of chronological age were non-responders. We found a significant correlation (P&lt;0.05) between vascular age and non-response to treatment.Conclusions: The majority (98.6%) of our patients had vascular age more than 80 years due to various risk factors of cardio vascular disease. Non-responsiveness to therapy showed a significant relationship with vascular age.

Reactive oxygen species, vascular Noxs, and hypertension: focus on translational and clinical research.

Reactive oxygen species (ROS) are signaling molecules that are important in physiological processes, including host defense, aging, and cellular homeostasis. Increased ROS bioavailability and altered redox signaling (oxidative stress) have been implicated in the onset and/or progression of chronic diseases, including hypertension. Although oxidative stress may not be the only cause of hypertension, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors, such as salt loading, activation of the renin-angiotensin-aldosterone system, and sympathetic hyperactivity, at least in experimental models. A major source for ROS in the cardiovascular-renal system is a family of nicotinamide adenine dinucleotide phosphate oxidases (Noxs), including the prototypic Nox2-based Nox, and Nox family members: Nox1, Nox4, and Nox5. Although extensive experimental data support a role for increased ROS levels and altered redox signaling in the pathogenesis of hypertension, the role in clinical hypertension is unclear, as a direct causative role of ROS in blood pressure elevation has yet to be demonstrated in humans. Nevertheless, what is becoming increasingly evident is that abnormal ROS regulation and aberrant signaling through redox-sensitive pathways are important in the pathophysiological processes which is associated with vascular injury and target-organ damage in hypertension. There is a paucity of clinical information related to the mechanisms of oxidative stress and blood pressure elevation, and a few assays accurately measure ROS directly in patients. Such further ROS research is needed in humans and in the development of adequately validated analytical methods to accurately assess oxidative stress in the clinic.

Reactive oxygen species and vascular biology: implications in human hypertension

Increased vascular production of reactive oxygen species (ROS; termed oxidative stress) has been implicated in various chronic diseases, including hypertension. Oxidative stress is both a cause and a consequence of hypertension. Although oxidative injury may not be the sole etiology, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors. Oxidative stress is a multisystem phenomenon in hypertension and involves the heart, kidneys, nervous system, vessels and possibly the immune system. Compelling experimental and clinical evidence indicates the importance of the vasculature in the pathophysiology of hypertension and as such much emphasis has been placed on the (patho)biology of ROS in the vascular system. A major source for cardiovascular, renal and neural ROS is a family of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), including the prototypic Nox2 homolog-based NADPH oxidase, as well as other Noxes, such as Nox1 and Nox4. Nox-derived ROS is important in regulating endothelial function and vascular tone. Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis and rarefaction, important processes involved in vascular remodeling in hypertension. Despite a plethora of data implicating oxidative stress as a causative factor in experimental hypertension, findings in human hypertension are less conclusive. This review highlights the importance of ROS in vascular biology and focuses on the potential role of oxidative stress in human hypertension.

The regulation of proximal tubular salt transport in hypertension: an update

Renal proximal tubular sodium reabsorption is regulated by sodium transporters, including the sodium glucose transporter, sodium amino acid transporter, sodium hydrogen exchanger isoform 3 and sodium phosphate cotransporter type 2 located at the luminal/apical membrane, and sodium bicarbonate cotransporter and Na+/K+ATPase located at the basolateral membrane. This review summarizes recent studies on sodium transporters that play a major role in the increase in blood pressure in essential/polygenic hypertension. Sodium transporters and Na+/K+ATPase are segregated in membrane lipid and nonlipid raft microdomains that regulate their activities and trafficking via cytoskeletal proteins. The increase in renal proximal tubule ion transport in polygenic hypertension is primarily due to increased activity of NHE3 and Cl/HCO3 exchanger at the luminal/apical membrane and a primary or secondary increase in Na+/K+ATPase activity. The increase in renal proximal tubule ion transport in hypertension is due to increased actions by prohypertensive factors that are unopposed by antihypertensive factors.

Salt sensitivity of blood pressure in NKCC1-deficient mice

NKCC1 is a widely expressed isoform of the Na-2Cl-K cotransporter that mediates several direct and indirect vascular effects and regulates expression and release of renin. In this study, we used NKCC1-deficient (NKCC1-/-) and wild-type (WT) mice to assess day/night differences of blood pressure (BP), locomotor activity, and renin release and to study the effects of high (8%) or low (0.03%) dietary NaCl intake on BP, activity, and the renin/aldosterone system. On a standard diet, 24-h mean arterial blood pressure (MAP) and heart rate determined by radiotelemetry, and their day/night differences, were not different in NKCC1-/- and WT mice. Spontaneous and wheel-running activities in the active night phase were lower in NKCC1-/- than WT mice. In NKCC1-/- mice on a high-NaCl diet, MAP increased by 10 mmHg in the night without changes in heart rate. In contrast, there was no salt-dependent blood pressure change in WT mice. MAP reductions by hydralazine (1 mg/kg) or isoproterenol (10 microg/mouse) were significantly greater in NKCC1-/- than WT mice. Plasma renin (PRC; ng ANG I.ml(-1).h(-1)) and aldosterone (aldo; pg/ml) concentrations were higher in NKCC1-/- than WT mice (PRC: 3,745+/-377 vs. 1,245+/-364; aldo: 763+/-136 vs. 327+/-98). Hyperreninism and hyperaldosteronism were found in NKCC1-/- mice during both day and night. High Na suppressed PRC and aldosterone in both NKCC1-/- and WT mice, whereas a low-Na diet increased PRC and aldosterone in WT but not NKCC1-/- mice. We conclude that 24-h MAP and MAP circadian rhythms do not differ between NKCC1-/- and WT mice on a standard diet, probably reflecting a balance between anti- and prohypertensive factors, but that blood pressure of NKCC1-/- mice is more sensitive to increases and decreases of Na intake.

Chronic intermittent hypoxia (CIH) enhances the lumbar sympathoexcitatory response to central hyperosmotic NaCl

Rats exposed to CIH develop elevated mean arterial pressure (MAP) and sympathetic nerve activity (SNA). Although pro-hypertensive factors such as stress and obesity have been implicated in responses to CIH, little is known regarding interactions of CIH with central effects of Na/osmolality. To investigate this issue, rats were exposed to alternating 3 min periods of normoxia (room air, 21% O2) and hypoxia (10% O2) for 8 hr/day for 7 days. Control rats continuously breathed normoxic air. Rats were then anesthetized and responses of MAP, renal and lumbar SNA to internal carotid artery injection (100 μl) of isotonic (150 mM) and hypertonic (450 mM) NaCl solutions were recorded. In control (n=7) and CIH-exposed (n=7) rats, ICA injection of isotonic NaCl was without effect on all recorded variables. In contrast, ICA injection of hypertonic NaCl significantly increased MAP (P<0.01), renal SNA (P<0.01–0.001) and lumbar SNA (P<0.01–0.001) in control and CIH-exposed rats. When compared across groups, the magnitude of MAP (control: 36±4 mmHg, CIH: 33±4 mmHg) and renal SNA (control: 191±12%, CIH: 194±16%) responses were similar. In contrast, the increase in lumbar SNA was significantly (P<0.05) greater in CIH-exposed (213±32%) rats compared to controls (153±8%). These data suggest that exaggerated sympathetic outflow following CIH may involve central interactions with Na/hyperosmolality. Specifically, CIH may sensitize those neural elements responsive to Na/hyperosmolality that regulate lumbar SNA. Support: HL071645 (GMT), HL66335 (SWM)

Changes in systolic arterial blood pressure in normal and spontaneously hypertensive rats produced by acute administration of inhibitors of prostaglandin biosynthesis

Six non-steroidal agents having the property of being able to inhibit prostaglandin (PG) biosynthesis or action were tested for their ability to affect systolic blood pressure in unanesthetized normotensive (WKY) and Spontaneously Hypertensive Rats (SHR). In WKY and pre-hypertensive young SHR, s.c. injection of indomethacin (1.0 mg/kg) had no significant effect on blood pressure measured 30 minutes after injection. In older SHR, indomethacin (15 mg/kg) caused a significant pressor response, while in age - matched WKY, this dose had no significant effect. Indomethacin also showed a prohypertensive action in 10–14, 23–38 and 23–27 week old SHR with doses of 1.0 and 3.0 mg/kg, respectively. Tiaramide (5 mg/kg), ETYA (5 mg/kg), tolmetin (25 mg/kg), and meclofanamate (15 mg/kg) caused a significant elevation of blood pressure in mature (7–8 month old) SHR. Age matched WKY showed no significant response to the same doses of these four agents. Fenoprofen (75 mg/kg) caused a significant elevation in pressure in 12–13 week old SHR which persisted for at least 2 hours. Tiaramide had no significant effect on pre-hypertensive SHR. The results are consistent with the concept that inhibition of prostaglandin synthesis may result in a diminished turnover of antihypertensive prostaglandins in SHR which are being elaborated in response to the hypertensive state. In normal rats and pre-hypertensive SHR, inhibition of prostaglandin synthesis or function may not result in a hypertensive response since pro-hypertensive factors either are absent, or other antihypertensive substances may still predominate to help maintain normal blood pressure.