Direct myoendothelial contacts in human pulmonary microvessels

Edhf 2000 ◽  
2003 ◽  
pp. 115-122
Keyword(s):  
Pulmonary Microvessels

Abrogation of thrombin-induced increase in pulmonary microvascular permeability in PAR-1 knockout mice

2000 ◽  
Vol 4 (2) ◽  
pp. 137-145 ◽  
Author(s):  
STEPHEN M. VOGEL ◽  
XIAOPEI GAO ◽  
DOLLY MEHTA ◽  
RICHARD D. YE ◽  
THERESA A. JOHN ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Microvascular Permeability ◽  
Agonist Peptide ◽  
Vasoconstrictor Response ◽  
Permeability Surface ◽  
Wet Weight ◽  
Microvessel Permeability ◽  
Pulmonary Microvessels ◽  
High Concentrations ◽  
Area Product

We investigated the function of proteinase-activated receptor-1 (PAR-1) in the regulation of pulmonary microvascular permeability in response to thrombin challenge using PAR-1 knockout mice (−/−). Lungs were isolated and perfused with albumin (5 g/100 ml)-Krebs solution at constant flow (2 ml/min). Lung wet weight and pulmonary artery pressure (Ppa) were continuously monitored. We determined the capillary filtration coefficient ( Kfc) and125I-labeled albumin (BSA) permeability-surface area product (PS) to assess changes in pulmonary microvessel permeability to liquid and albumin, respectively. Normal and PAR-1-null lung preparations received in the perfusate: 1) thrombin or 2) selective PAR-1 agonist peptide (TFLLRNPNDK-NH2). In control PAR-1 (+/+) mouse lungs,125I-albumin PS and Kfcwere significantly increased over baseline (by ∼7- and 1.5-fold, respectively) within 20 min of α-thrombin (100 nM) challenge. PAR-1 agonist peptide (5 μM) gave similar results, whereas control peptide (5 μM; FTLLRNPNDK-NH2) was ineffective. At relatively high concentrations, thrombin (500 nM) or PAR-1 agonist peptide (10 μM) also induced increases in Ppaand lung wet weight. All effects of thrombin (100 or 500 nM) or PAR-1 agonist peptide (5 or 10 μM) were prevented in PAR-1-null lung preparations. Baseline measures of microvessel permeability and Ppain the PAR-1-null preparations were indistinguishable from those in normal lungs. Moreover, PAR-1-null preparations gave normal vasoconstrictor response to thromboxane analog, U-46619 (100 nM). The results indicate that the PAR-1 receptor is critical in mediating the permeability-increasing and vasoconstrictor effects of thrombin in pulmonary microvessels.

Evidence for active control of perfusion within lung microvessels

2012 ◽  
Vol 112 (1) ◽  
pp. 48-53 ◽  
Author(s):  
Kal E. Watson ◽  
William F. Dovi ◽  
Robert L. Conhaim
Keyword(s):  
Endothelial Cells ◽  
Angiotensin Ii ◽  
Active Control ◽  
Microvascular Perfusion ◽  
Microvascular Endothelial Cells ◽  
Common Mechanism ◽  
Cells In Culture ◽  
Rat Lungs ◽  
Pulmonary Microvessels

Vasoconstrictors cause contraction of pulmonary microvascular endothelial cells in culture. We wondered if this meant that contraction of these cells in situ caused active control of microvascular perfusion. If true, it would mean that pulmonary microvessels were not simply passive tubes and that control of pulmonary microvascular perfusion was not mainly due to the contraction and dilation of arterioles. To test this idea, we vasoconstricted isolated perfused rat lungs with angiotensin II, bradykinin, serotonin, or U46619 (a thromboxane analog) at concentrations that produced equal flows. We also perfused matched-flow controls. We then infused a bolus of 3 μm diameter particles into each lung and measured the rate of appearance of the particles in the venous effluent. We also measured microscopic trapping patterns of particles retained within each lung. Thirty seconds after particle infusion, venous particle concentrations were significantly lower ( P ≤ 0.05) for lungs perfused with angiotensin II or bradykinin than for those perfused with U46619, but not significantly different from serotonin perfused lungs or matched flow controls. Microscopic clustering of particles retained within the lungs was significantly greater ( P ≤ 0.05) for lungs perfused with angiotensin II, bradykinin, or serotonin, than for lungs perfused with U46619 or for matched flow controls. Our results suggest that these agents did not produce vasoconstriction by a common mechanism and support the idea that pulmonary microvessels possess a level of active control and are not simply passive exchange vessels.

Segmental barrier properties of the pulmonary microvascular bed

1991 ◽  
Vol 71 (6) ◽  
pp. 2152-2159 ◽  
Author(s):  
R. L. Qiao ◽  
J. Bhattacharya
Keyword(s):  
Barrier Properties ◽  
Vessel Diameter ◽  
Unit Surface Area ◽  
Liquid Transport ◽  
Liquid Flux ◽  
Unit Surface ◽  
Pulmonary Microvessels ◽  
Pentobarbital Sodium Anesthesia ◽  
Area X ◽  
Drop Technique

We determined liquid flux across single pulmonary microvessels of dog, ferret, and rat by our split-drop technique (J. Appl. Physiol. 64: 2562–2567, 1988). Data are reported from 58 lungs excised under halothane or pentobarbital sodium anesthesia and then blood perfused. We stopped blood flow at known vascular pressures and then micropunctured microvessels to inject oil, which we split with albumin solution. From measurements of vessel diameter and split oil drop length, we calculated Jv, the liquid transport rate per unit surface area [x 10(-6) ml/(cm2.s)]. At constant vascular pressure, Jv was not significantly different after different periods of oil-endothelium contact and at different sites within a single vessel. From measurements of Jv at different vascular pressures, we determined Lp, the hydraulic conductivity [x 10(-7) ml/(cm2.s.cmH2O)], and Pzf, the zero filtration pressure. From determinations of Pzf at different albumin concentrations, we quantified sigma alb, the albumin reflection coefficient. Lp and Pzf did not differ among venules of the same lung. However, in venules, Lp was 40% higher and sigma alb 25% lower than in arterioles (P less than 0.01). We conclude that 1) micropuncture procedures incidental to our split-drop technique do not progressively deteriorate the experimental microvessel and 2) in lung, permeability is higher in venules than in arterioles.

scholarly journals PPARγ-p53-Mediated Vasculoregenerative Program to Reverse Pulmonary Hypertension

2020 ◽  
Author(s):  
Jan K Hennigs ◽  
Aiqin Cao ◽  
Caiyun G Li ◽  
Minyi Shi ◽  
Julia Mienert ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Pulmonary Hypertension ◽  
Transcription Factor ◽  
Excision Repair ◽  
Oxidant Stress ◽  
Chip Sequencing ◽  
Pulmonary Arterial ◽  
Pulmonary Microvessels ◽  
Transcription Factor Complex

Rationale: In pulmonary arterial hypertension (PAH), endothelial dysfunction and obliterative vascular disease are associated with DNA damage and impaired signaling of bone morphogenetic protein type 2 receptor (BMPR2) via two downstream transcription factors, PPARγ and p53. Objective: We investigated the vasculoprotective and regenerative potential of a newly identified PPARγ- p53 transcription factor complex in the pulmonary endothelium. Methods and Results: In this study, we identified a pharmacologically inducible vasculoprotective mechanism in pulmonary arterial (PA) and lung microvascular (MV) endothelial cells (EC) in response to DNA damage and oxidant stress regulated in part by a BMPR2 dependent transcription factor complex between PPARγ and p53. Chromatin immunoprecipitation (ChIP) sequencing (seq) and RNA-seq established an inducible PPARγ-p53 mediated regenerative program regulating 19 genes involved in lung EC survival, angiogenesis and DNA repair including, EPHA2, FHL2, JAG1, SULF2 and TIGAR. Expression of these genes was partially impaired when the PPARγ-p53 complex was pharmacologically disrupted or when BMPR2 was reduced in PAEC subjected to oxidative stress. In EC-Bmpr2-knockout mice unable to stabilize p53 in ECs under oxidative stress, Nutlin-3 rescued endothelial p53 and PPARγ-p53 complex formation and induced target genes, such as APLN and JAG1, to regenerate pulmonary microvessels and reverse pulmonary hypertension. In PAEC from BMPR2 mutant PAH patients, pharmacological induction of p53 and PPARγ-p53 genes repaired damaged DNA utilizing genes from the nucleotide excision repair pathway without provoking PAEC apoptosis. Conclusions: We identified a novel therapeutic strategy that activates a vasculoprotective gene regulation program in PAEC downstream of dysfunctional BMPR2 to rehabilitate PAH PAEC, regenerate pulmonary microvessels and reverse disease. Our studies pave the way for p53-based vasculoregenerative therapies for PAH by extending the therapeutic focus to PAEC dysfunction and to DNA damage associated with PAH progression.

Pulmonary microcirculatory response to localized hypercapnia

1982 ◽  
Vol 53 (6) ◽  
pp. 1556-1564 ◽  
Author(s):  
T. Koyama ◽  
M. Horimoto
Keyword(s):  
Flow Velocity ◽  
Time Course ◽  
Capillary Flow ◽  
Mean Flow ◽  
Velocity Change ◽  
Luminal Diameter ◽  
Initial Values ◽  
Pulmonary Capillary ◽  
Before And After ◽  
Pulmonary Microvessels

Anesthetized bullfrogs were examined to study the effects of localized hypercapnia on the red blood cell (RBC) velocity in pulmonary alveolar microvessels on the exposed lung surface. Before and after the exposure of a small area of the lung surface 6 mm in diameter to a hypercapnic gas mixture, the region was exposed to CO2-free control gas. The RBC velocity was measured by the use of a laser Doppler microscope. Both mean flow velocity (MV) and pulsatile amplitude (PA) were determined from the resulting flow velocity contour. Responses of pulmonary microvessels to hypercapnia were examined by measuring the vessel diameters with an ocular microscale of the microscope while gas mixtures were applied to a 1-mm-diameter region of the surface. During hypercapnia both MV (2.31 +/- 0.27 mm/s) and PA (0.54 +/- 0.15 mm/s) in the alveolar arterioles (luminal diameter = 64 +/- 14 microns) were reduced, each reaching a minimum (2.01 +/- 0.24 and 0.43 +/- 0.19 mm/s, respectively) prior to gradual returns to their initial values. After reintroduction of the control gas, the values of MV and PA approached initial values more rapidly. In capillaries MV (1.44 +/- 0.18 mm/s) and PA (0.28 +/- 0.06 mm/s) decreased to 1.25 +/- 0.10 and 0.15 +/- 0.05 mm/s, respectively. The maximum reduction of PA (-44.6%) therefore clearly exceeded that of MV (-12.4%) in capillary flow. An analog model calculation suggested that the reduction in diameter of the arteriolar system could reduce PA more than MV in the pulmonary capillary network. The time course of the velocity change closely resembled that of the diameter change in relatively large arterioles. Vasoconstriction of the arterioles therefore appeared to be the major cause of these decrements in MV and PA.

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