bims-heshmo 2021-07-04 papers

bims-heshmo

Biomed News

on Trauma hemorrhagic shock — molecular basis

Issue of 2021‒07‒04
fourteen papers selected by
Andreia Luís
Ludwig Boltzmann Institute

Complications of Hemorrhagic Shock and Massive Transfusion-a Comparison Before and After the Damage Control Resuscitation Era.
The Role of DAMPS in Burns and Hemorrhagic Shock Immune Response: Pathophysiology and Clinical Issues. Review.
Cellular Signal Transduction Pathways Involved in Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion.
Prolonged Chronic Stress and Persistent Iron Dysregulation Prevent Anemia Recovery Following Trauma.
Focal intra-colon cooling reduces organ injury and systemic inflammation after REBOA management of lethal hemorrhage in rats.
Sulforaphane Ameliorates the Liver Injury of Traumatic Hemorrhagic Shock Rats.
Hypoxic mesenchymal stem cells ameliorate acute kidney ischemia-reperfusion injury via enhancing renal tubular autophagy.
Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis.
Embryonic stem cell-derived extracellular vesicles promote the recovery of kidney injury.
Vasoactive therapy in shock.
White Blood Cell and Platelet Dynamics Define Human Inflammatory Recovery.
Systemic T Cell Exhaustion Dynamics Is Linked to Early High Mobility Group Box Protein 1 (HMGB1) Driven Hyper-Inflammation in a Polytrauma Rat Model.
Acute kidney injury in the critically ill: an updated review on pathophysiology and management.
Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.

Shock. 2021 Jul 01. 56(1): 42-51

Complications of Hemorrhagic Shock and Massive Transfusion-a Comparison Before and After the Damage Control Resuscitation Era.

Jonathan A Black, Virginia S Pierce, Kavina Juneja, John B Holcomb.

ABSTRACT: Trauma remains a leading cause of death, and hemorrhage is the leading cause of preventable trauma deaths. Resuscitation strategies in trauma have changed dramatically over the last 20 years. In the pre damage control resuscitation (DCR) era, we used large volume crystalloid resuscitation and packed red blood cells as the primary resuscitative fluids. Now, a 1:1:1 ratio of packed red blood cells, fresh plasma, and platelets with minimal crystalloids is the preferred resuscitative strategy (DCR era). As we have changed how we resuscitate patients, the detrimental effects associated with large volume resuscitation have also changed. In this article, we review the effects of large volume blood product resuscitation, and where possible present a contrast between the pre-DCR era and the DCR era resuscitation strategies.

DOI: https://doi.org/10.1097/SHK.0000000000001676
Int J Mol Sci. 2021 Jun 29. pii: 7020. [Epub ahead of print]22(13):

The Role of DAMPS in Burns and Hemorrhagic Shock Immune Response: Pathophysiology and Clinical Issues. Review.

Desirè Pantalone, Carlo Bergamini, Jacopo Martellucci, Giovanni Alemanno, Alessandro Bruscino, Gherardo Maltinti, Maximilian Sheiterle, Riccardo Viligiardi, Roberto Panconesi, Tommaso Guagni, Paolo Prosperi.

  Severe or major burns induce a pathophysiological, immune, and inflammatory response that can persist for a long time and affect morbidity and mortality. Severe burns are followed by a "hypermetabolic response", an inflammatory process that can be extensive and become uncontrolled, leading to a generalized catabolic state and delayed healing. Catabolism causes the upregulation of inflammatory cells and innate immune markers in various organs, which may lead to multiorgan failure and death. Burns activate immune cells and cytokine production regulated by damage-associated molecular patterns (DAMPs). Trauma has similar injury-related immune responses, whereby DAMPs are massively released in musculoskeletal injuries and elicit widespread systemic inflammation. Hemorrhagic shock is the main cause of death in trauma. It is hypovolemic, and the consequence of volume loss and the speed of blood loss manifest immediately after injury. In burns, the shock becomes evident within the first 24 h and is hypovolemic-distributive due to the severely compromised regulation of tissue perfusion and oxygen delivery caused by capillary leakage, whereby fluids shift from the intravascular to the interstitial space. In this review, we compare the pathophysiological responses to burns and trauma including their associated clinical patterns.

Keywords:  DAMPs; alarmin; burns; cytokine production; hemorrhagic shock; shock; trauma

DOI:  https://doi.org/10.3390/ijms22137020
Oxid Med Cell Longev. 2021 ;2021 9985701

Cellular Signal Transduction Pathways Involved in Acute Lung Injury Induced by Intestinal Ischemia-Reperfusion.

Guangyao Li, Yingyi Zhang, Zhe Fan.

Intestinal ischemia-reperfusion (II/R) injury is a common type of tissue and organ injury, secondary to intestinal and mesenteric vascular diseases. II/R is characterized by a high incidence rate and mortality. In the II/R process, intestinal barrier function is impaired and bacterial translocation leads to excessive reactive oxygen species, inflammatory cytokine release, and even apoptosis. A large number of inflammatory mediators and oxidative factors are released into the circulation, leading to severe systemic inflammation and multiple organ failure of the lung, liver, and kidney. Acute lung injury (ALI) is the most common complication, which gradually develops into acute respiratory distress syndrome and is the main cause of its high mortality. This review summarizes the signal transduction pathways and key molecules in the pathophysiological process of ALI induced by II/R injury and provides a new therapeutic basis for further exploration of the molecular mechanisms of ALI induced by II/R injury. In particular, this article will focus on the biomarkers involved in II/R-induced ALI.

DOI: https://doi.org/10.1155/2021/9985701
J Surg Res. 2021 Jun 26. pii: S0022-4804(21)00348-6. [Epub ahead of print]267 320-327

Prolonged Chronic Stress and Persistent Iron Dysregulation Prevent Anemia Recovery Following Trauma.

Camille G Apple, Elizabeth S Miller, Kolenkode B Kannan, Chase Thompson, Dijoia B Darden, Philip A Efron, Alicia M Mohr.

  Introduction Following major trauma, persistent injury-associated anemia is associated with organ failure, increased length of stay and mortality. We hypothesize that prolonged adrenergic stimulation following trauma is directly responsible for persistent iron dysfunction that impairs anemia recovery. Materials and Methods Naïve rodents, lung contusion and hemorrhagic shock followed by daily handling for 13 d (LCHS), LCHS followed by 6 d of restraint stress and 7 d of daily handling (LCHS/CS-7) and LCHS/CS followed by 13 d of restraint stress with day and/or night disruption (LCHS/CS-14) were sacrificed on day 14. Hemoglobin, plasma, urine, bone marrow/liver inflammatory and erythropoietic markers were analyzed. Results LCHS/CS-14 led to a significant decline in weight gain and persistently elevated plasma and urine inflammatory markers. Liver IL-6, IL-1β and hepcidin expression were significantly increased following LCHS/CS-14. LCHS/CS-14 also had impaired anemia recovery with reduced plasma transferrin and erythropoietin receptor expression. Conclusion Prolonged chronic stress following trauma/hemorrhagic shock led to sustained inflammation with increased expression of IL-1β, IL-6 and hepcidin with decreased iron availability for uptake into erythroid progenitor cells and a lack of anemia recovery.

Keywords:  Erythropoiesis; Hepcidin; IL-1β; IL-6; Inflammation

DOI:  https://doi.org/10.1016/j.jss.2021.05.034
Sci Rep. 2021 Jul 01. 11(1): 13696

Focal intra-colon cooling reduces organ injury and systemic inflammation after REBOA management of lethal hemorrhage in rats.

Awadhesh K Arya, Kurt Hu, Lalita Subedi, Tieluo Li, Bingren Hu.

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving maneuver for the management of lethal torso hemorrhage. However, its prolonged use leads to distal organ ischemia-reperfusion injury (IRI) and systemic inflammatory response syndrome (SIRS). The objective of this study is to investigate the blood-based biomarkers of IRI and SIRS and the efficacy of direct intestinal cooling in the prevention of IRI and SIRS. A rat lethal hemorrhage model was produced by bleeding 50% of the total blood volume. A balloon catheter was inserted into the aorta for the implementation of REBOA. A novel TransRectal Intra-Colon (TRIC) device was placed in the descending colon and activated from 10 min after the bleeding to maintain the intra-colon temperature at 37 °C (TRIC37°C group) or 12 °C (TRIC12°C group) for 270 min. The upper body temperature was maintained at as close to 37 °C as possible in both groups. Blood samples were collected before hemorrhage and after REBOA. The organ injury biomarkers and inflammatory cytokines were evaluated by ELISA method. Blood based organ injury biomarkers (endotoxin, creatinine, AST, FABP1/L-FABP, cardiac troponin I, and FABP2/I-FABP) were all drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated these increased organ injury biomarkers. Plasma levels of pro-inflammatory cytokines TNF-α, IL-1b, and IL-17F were also drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated the pro-inflammatory cytokines. In contrast, TRIC12°C significantly upregulated the levels of anti-inflammatory cytokines IL-4 and IL-10 after REBOA. Amazingly, the mortality rate was 100% in TRIC37°C group whereas 0% in TRIC12°C group after REBOA. Directly cooling the intestine offered exceptional protection of the abdominal organs from IRI and SIRS, switched from a harmful pro-inflammatory to a reparative anti-inflammatory response, and mitigated mortality in the rat model of REBOA management of lethal hemorrhage.

DOI: https://doi.org/10.1038/s41598-021-93064-4
J Surg Res. 2021 Jun 22. pii: S0022-4804(21)00302-4. [Epub ahead of print]267 293-301

Sulforaphane Ameliorates the Liver Injury of Traumatic Hemorrhagic Shock Rats.

Zhihui Guan, Lingmin Zhou, Yu Zhang, Yu Zhang, Hongping Chen, Feifei Shao.

  BACKGROUND: The protective effects of sulforaphane on liver injury induced by high-fat diet and sodium valproate were previously reported. The present study preliminarily investigated the effect of sulforaphane on liver injury induced by traumatic hemorrhagic shock.MATERIALS AND METHODS: After a traumatic hemorrhagic shock model was established in rats, the survival of rats during the first 24 hours was analyzed by Kaplan-Meier analysis. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), tumor necrosis factor α (TNF-α), and interleukin 1β (IL-1β) were measured using a biochemical analyzer or enzyme-linked immunosorbent assay (ELISA). The cell apoptosis and histopathology of liver tissues were examined by TUNEL and hematoxylin-eosin (HE) staining. The mRNA and protein expressions of B-cell lymphoma-2 (Bcl-2), Bcl2 associated X (Bax), Caspase-3, TNF-α, IL-1β, Cyclooxygenase-2 (COX-2), nitric oxide synthase (iNOS), nuclear factor E2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) in the liver tissues were determined by immunohistochemical staining, quantitative reverse transcription PCR (qRT-PCR) or western blot.
RESULTS: Sulforaphane promoted the health of the animal, reduced liver cell apoptosis and ameliorated the histopathological damage in the liver of rats with traumatic hemorrhagic shock. Sulforaphane downregulated the expressions of liver function-related factors (ALT, AST, TB), inflammation-related factors (TNF-α, IL-1β, COX-2, iNOS), and apoptosis-related factors (Bax, Caspase-3) and upregulated the expressions of factors related to apoptosis (Bcl-2) and Nrf2/HO-1 pathway (Nrf2, HO-1).
CONCLUSION: Sulforaphane protected the liver against traumatic hemorrhagic shock through ameliorating the apoptosis and inflammation of the liver via activating the Nrf2/HO-1 pathway.

Keywords:  Apoptosis; Inflammation; Liver injury; Nrf2/HO-1 pathway; Sulforaphane; Traumatic hemorrhagic shock

DOI:  https://doi.org/10.1016/j.jss.2021.05.004
Stem Cell Res Ther. 2021 Jun 28. 12(1): 367

Hypoxic mesenchymal stem cells ameliorate acute kidney ischemia-reperfusion injury via enhancing renal tubular autophagy.

Wei-Cheng Tseng, Pei-Ying Lee, Ming-Tsun Tsai, Fu-Pang Chang, Nien-Jung Chen, Chiang-Ting Chien, Shih-Chieh Hung, Der-Cherng Tarng.

  BACKGROUND: Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear.METHODS: Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI.
RESULT: HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1β, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery.
CONCLUSION: The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI.

Keywords:  Acute kidney injury; Autophagy; Hypoxic mesenchymal stem cells; Ischemia-reperfusion injury

DOI:  https://doi.org/10.1186/s13287-021-02374-x
Semin Immunopathol. 2021 Jun 30.

Complement as driver of systemic inflammation and organ failure in trauma, burn, and sepsis.

Marco Mannes, Christoph Q Schmidt, Bo Nilsson, Kristina N Ekdahl, Markus Huber-Lang.

  Complement is one of the most ancient defense systems. It gets strongly activated immediately after acute injuries like trauma, burn, or sepsis and helps to initiate regeneration. However, uncontrolled complement activation contributes to disease progression instead of supporting healing. Such effects are perceptible not only at the site of injury but also systemically, leading to systemic activation of other intravascular cascade systems eventually causing dysfunction of several vital organs. Understanding the complement pathomechanism and its interplay with other systems is a strict requirement for exploring novel therapeutic intervention routes. Ex vivo models exploring the cross-talk with other systems are rather limited, which complicates the determination of the exact pathophysiological roles that complement has in trauma, burn, and sepsis. Literature reporting on these three conditions is often controversial regarding the importance, distribution, and temporal occurrence of complement activation products further hampering the deduction of defined pathophysiological pathways driven by complement. Nevertheless, many in vitro experiments and animal models have shown beneficial effects of complement inhibition at different levels of the cascade. In the future, not only inhibition but also a complement reconstitution therapy should be considered in prospective studies to expedite how meaningful complement-targeted interventions need to be tailored to prevent complement augmented multi-organ failure after trauma, burn, and sepsis.This review summarizes clinically relevant studies investigating the role of complement in the acute diseases trauma, burn, and sepsis with important implications for clinical translation.

Keywords:  Burn; Clinical translation; Complement activation; Sepsis; Systemic inflammation; Thromboinflammation; Trauma

DOI:  https://doi.org/10.1007/s00281-021-00872-x
Stem Cell Res Ther. 2021 Jul 02. 12(1): 379

Embryonic stem cell-derived extracellular vesicles promote the recovery of kidney injury.

Lu Yu, Siying Liu, Chen Wang, Chuanyu Zhang, Yajie Wen, Kaiyue Zhang, Shang Chen, Haoyan Huang, Yue Liu, Lingling Wu, Zhongchao Han, Xiangmei Chen, Zongjin Li, Na Liu.

  BACKGROUND: Embryonic stem cell-derived extracellular vesicles (ESC-EVs) possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury (AKI) is a common acute and severe disease in clinical practice, which seriously threatens human life and health. However, the roles and mechanisms of ESC-EVs on AKI remain unclear.METHODS: In this study, we evaluated the effects of ESC-EVs on physiological repair and pathological repair using murine ischemia-reperfusion injury-induced AKI model, the potential mechanisms of which were next investigated. EVs were isolated from ESCs and EVs derived from mouse fibroblasts as therapeutic controls. We then investigated whether ESC-EVs can restore the structure and function of the damaged kidney by promoting physiological repair and inhibiting the pathological repair process after AKI in vivo and in vitro.
RESULTS: We found that ESC-EVs significantly promoted the recovery of the structure and function of the damaged kidney. ESC-EVs increased the proliferation of renal tubular epithelial cells, facilitated renal angiogenesis, inhibited the progression of renal fibrosis, and rescued DNA damage caused by ischemia and reperfusion after AKI. Finally, we found that ESC-EVs play a therapeutic effect by activating Sox9+ cells.
CONCLUSIONS: ESC-EVs significantly promote the physiological repair and inhibit the pathological repair after AKI, enabling restoration of the structure and function of the damaged kidney. This strategy might emerge as a novel therapeutic strategy for ESC clinical application.

Keywords:  Acute kidney injury (AKI); Embryonic stem cell (ESC); Extracellular vesicles (EVs); Pathological repair; Physiological repair

DOI:  https://doi.org/10.1186/s13287-021-02460-0
BJA Educ. 2021 Jul;21(7): 270-277

Vasoactive therapy in shock.

A Jha, G Zilahi, A Rhodes.



Keywords:  noradrenaline; sepsis; shock; vasopressor agents

DOI:  https://doi.org/10.1016/j.bjae.2021.03.002
medRxiv. 2021 Jun 23. pii: 2021.06.19.21259181. [Epub ahead of print]

White Blood Cell and Platelet Dynamics Define Human Inflammatory Recovery.

Brody H Foy, Thor Sundt, Jonathan C T Carlson, Aaron D Aguirre, John M Higgins.

Inflammation is the physiologic reaction to cellular and tissue damage caused by pathologic processes including trauma, infection, and ischemia 1 . Effective inflammatory responses integrate molecular and cellular functions to prevent further tissue damage, initiate repair, and restore homeostasis, while futile or dysfunctional responses allow escalating injury, delay recovery, and may hasten death 2 . Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not established 3,4 . Patient responses appear to vary dramatically with no clearly defined signs of good prognosis, leaving physicians reliant on qualitative interpretations of laboratory trends 4,5 . We retrospectively, observationally studied the human acute inflammatory response to trauma, ischemia, and infection by tracking the longitudinal dynamics of cellular and serum markers in hospitalized patients. Unexpectedly, we identified a conserved pattern of recovery defined by co-regulation of WBC and platelet (PLT) populations. Across all inflammatory conditions studied, recovering patients followed a consistent WBC-PLT trajectory shape that is well-approximated by exponential WBC decay and delayed linear PLT growth. This recovery trajectory shape may represent a fundamental archetype of human physiologic response at the cellular population scale, and provides a generic approach for identifying high-risk patients: 32x relative risk of adverse outcomes for cardiac surgery patients, 9x relative risk of death for COVID-19, and 5x relative risk of death for myocardial infarction.

DOI: https://doi.org/10.1101/2021.06.19.21259181
Cells. 2021 Jun 30. pii: 1646. [Epub ahead of print]10(7):

Systemic T Cell Exhaustion Dynamics Is Linked to Early High Mobility Group Box Protein 1 (HMGB1) Driven Hyper-Inflammation in a Polytrauma Rat Model.

Preeti J Muire, Martin G Schwacha, Joseph C Wenke.

  We previously reported an early surge in high mobility group box protein 1 (HMGB1) levels in a polytrauma (PT) rat model. This study investigates the association of HMGB1 levels in mediating PT associated dysregulated immune responses and its influence on the cellular levels of receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). Using the same PT rat model treated with anti-HMGB1 polyclonal antibody, we evaluated changes in circulating inflammatory cytokines, monocytes/macrophages and T cells dynamics and cell surface expression of RAGE and TLR4 at 1, 3, and 7 days post-trauma (dpt) in blood and spleen. Notably, PT rats demonstrating T helper (Th)1 and Th2 cells type early hyper-inflammatory responses also exhibited increased monocyte/macrophage counts and diminished T cell counts in blood and spleen. In blood, expression of RAGE and TLR4 receptors was elevated on CD68+ monocyte/macrophages and severely diminished on CD4+ and CD8+ T cells. Neutralization of HMGB1 significantly decreased CD68+ monocyte/macrophage counts and increased CD4+ and CD8+ T cells, but not γδ+TCR T cells in circulation. Most importantly, RAGE and TLR4 expressions were restored on CD4+ and CD8+ T cells in treated PT rats. Overall, findings suggest that in PT, the HMGB1 surge is responsible for the onset of T cell exhaustion and dysfunction, leading to diminished RAGE and TLR4 surface expression, thereby possibly hindering the proper functioning of T cells.

Keywords:  DAMPs; RAGE; TLR4; extremity trauma; hyper-inflammation; lymphopenia

DOI:  https://doi.org/10.3390/cells10071646
Intensive Care Med. 2021 Jul 02.

Acute kidney injury in the critically ill: an updated review on pathophysiology and management.

Peter Pickkers, Michael Darmon, Eric Hoste, Michael Joannidis, Matthieu Legrand, Marlies Ostermann, John R Prowle, Antoine Schneider, Miet Schetz.

  Acute kidney injury (AKI) is now recognized as a heterogeneous syndrome that not only affects acute morbidity and mortality, but also a patient's long-term prognosis. In this narrative review, an update on various aspects of AKI in critically ill patients will be provided. Focus will be on prediction and early detection of AKI (e.g., the role of biomarkers to identify high-risk patients and the use of machine learning to predict AKI), aspects of pathophysiology and progress in the recognition of different phenotypes of AKI, as well as an update on nephrotoxicity and organ cross-talk. In addition, prevention of AKI (focusing on fluid management, kidney perfusion pressure, and the choice of vasopressor) and supportive treatment of AKI is discussed. Finally, post-AKI risk of long-term sequelae including incident or progression of chronic kidney disease, cardiovascular events and mortality, will be addressed.

Keywords:  Acute kidney injury; Biomarkers; Blood pressure management; Diagnosis; Fluid therapy; Heterogeneity; Long-term consequences; Machine learning; Nephrotoxicity; Organ cross-talk; Pathophysiology; Phenotypes; Vasopressor

DOI:  https://doi.org/10.1007/s00134-021-06454-7
Intensive Care Med Exp. 2021 Jun 11. 9(1): 28

Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.

Simon Lambden, Andrew S Cowburn, David Macias, Tessa A C Garrud, Bernardo J Krause, Dino A Giussani, Charlotte Summers, Randall S Johnson.

  BACKGROUND: The vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α. In vivo, arterial blood pressure and metabolic activity were monitored continuously in normal atmospheric conditions and following an acute stimulus with hypoxia (10%) or lipopolysaccharide (LPS). Ex vivo, femoral artery reactivity was assessed using wire myography.RESULTS: Under normoxia, the HIF-1α Tie2Cre mouse had increased systolic and diastolic arterial pressure compared to litter mate controls over the day-night cycle under normal environmental conditions. VO2 and VCO2 were also increased. Femoral arteries displayed impaired endothelial relaxation in response to acetylcholine mediated by a reduction in the nitric oxide dependent portion of the response. HIF-1α L1Cre mice displayed a similar pattern of increased systemic blood pressure, metabolic rate and impaired vascular relaxation without features of pulmonary hypertension, polycythaemia or renal dysfunction under normal conditions. In response to acute hypoxia, deficiency of HIF-1α was associated with faster resolution of hypoxia-induced haemodynamic and metabolic compromise. In addition, systemic haemodynamics were less compromised by LPS treatment.
CONCLUSIONS: These data show that deficiency of HIF-1α in the systemic or pulmonary endothelium is associated with increased systemic blood pressure and metabolic rate, a pattern that persists in both normoxic conditions and in response to acute stress with potential implications for our understanding of the pathophysiology of vascular dysfunction in acute and chronic disease.

Keywords:  Blood pressure; HIF-1α; HIF-2α; Haemodynamics; Metabolism; Vascular endothelium

DOI:  https://doi.org/10.1186/s40635-021-00390-y