VEGF121- and bFGF-induced increase in collateral blood flow requires normal nitric oxide production

2001 ◽  
Vol 280 (3) ◽  
pp. H1097-H1104 ◽  
Author(s):  
H. T. Yang ◽  
Z. Yan ◽  
Judith A. Abraham ◽  
Ronald L. Terjung
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Growth Factors ◽  
Growth Factor ◽  
Vascular Remodeling ◽  
No Production ◽  
Collateral Blood Flow ◽  
Angiogenic Growth Factors ◽  
Blood Flows ◽  
Calf Muscles

The angiogenic proteins basic fibroblast growth factor (bFGF; FGF-2) and vascular endothelial growth factor 121 (VEGF121) are each able to enhance the collateral-dependent blood flow after bilateral femoral artery ligation in rats. To study the effect of nitric oxide (NO) synthase (NOS) inhibition on bFGF- or VEGF121-induced blood flow expansion, the femoral arteries of male Sprague-Dawley rats were ligated bilaterally, and the animals were given tap water [non- NG-nitro-l-arginine methyl ester (l-NAME) group; n = 36] or water that contained l-NAME (l-NAME group; 2 mg/ml, n = 36). Animals from each group were further divided into three subgroups: vehicle ( n = 12), bFGF (5 μg · kg−1· day−1, n = 12), or VEGF121(10 μg · kg−1· day−1, n = 12). Growth factors were delivered via intra-arterial infusion with osmotic pumps over days 1–14. On day 16, after a 2-day delay to permit clearance of bFGF and VEGF from the circulation, maximal collateral blood flow was determined by85Sr- and141Ce-labeled microspheres during treadmill running.l-NAME (∼137 mg · kg−1· day−1) for 18 days increased systemic blood pressure (∼26%, P < 0.001). In the absence of l-NAME, collateral-dependent blood flows to the calf muscles were greater in the VEGF121- and bFGF-treated subgroups (85 ± 4.5 and 80 ± 2.9 ml · min−1· 100 g−1, respectively) than in the vehicle subgroup (49 ± 3.0 ml · min−1· 100 g−1, P < 0.001). In the presence of NOS inhibition byl-NAME, blood flows to the calf muscles were essentially equivalent among the three subgroups (54 ± 3.0, 56 ± 5.1, and 47 ± 2.0 ml · min−1· 100 g−1in the bFGF-, VEGF121-, and vehicle-treated subgroups, respectively) and were not different from the blood flow in the non-l-NAME vehicle subgroup. Our results therefore indicate that normal NO production is essential for the enhanced vascular remodeling induced by exogenous bFGF or VEGF121in this rat model of experimental peripheral arterial insufficiency. These results imply that a blunted endothelial NO production could temper vascular remodeling in response to these angiogenic growth factors.

scholarly journals Endogenous vascular remodeling in ischemic skeletal muscle: a role for nitric oxide

2003 ◽  
Vol 94 (3) ◽  
pp. 935-940 ◽  
Author(s):  
John B. Buckwalter ◽  
Valerie C. Curtis ◽  
Zoran Valic ◽  
Stephen B. Ruble ◽  
Philip S. Clifford
Keyword(s):  
Nitric Oxide ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Methyl Ester ◽  
Vascular Remodeling ◽  
Treated Group ◽  
No Synthase ◽  
No Production ◽  
Ischemic Limb ◽  
Time Flow

To test the hypothesis that nitric oxide (NO) production is essential for endogenous vascular remodeling in ischemic skeletal muscle, 22 New Zealand White rabbits were chronically instrumented with transit-time flow probes on the common iliac arteries and underwent femoral ligation to produce unilateral hindlimb ischemia. Iliac blood flow and arterial pressure were recorded at rest and during a graded exercise test. An osmotic pump connected to a femoral arterial catheter continuously delivered N-nitro-l-arginine methyl ester (a NO synthase inhibitor) or a control solution ( N-nitro-d-arginine methyl ester or phenylephrine) to the ischemic limb over a 2-wk period. At 1, 3, and 6 wk after femoral ligation, maximal treadmill exercise blood flow in the ischemic limb was reduced compared with baseline in each group. However, maximal exercise blood flow was significantly ( P < 0.05) lower in the l-NAME-treated group than in controls for the duration of the study: 48 ± 4 vs. 60 ± 5 ml/min at 6 wk. Consistent with the reduction in maximal blood flow response, the duration of voluntary exercise was also substantially ( P < 0.05) shorter in thel-NAME-treated group: 539 ± 67 vs. 889 ± 87 s. Resting blood flow was unaffected by femoral ligation in either group. The results of this study show that endogenous vascular remodeling, which partially alleviated the initial deficit in blood flow, was interrupted by NO synthase inhibition. Therefore, we conclude that NO is essential for endogenous collateral development and angiogenesis in ischemic skeletal muscle in the rabbit.

Efficacy and specificity of bFGF increased collateral flow in experimental peripheral arterial insufficiency

2000 ◽  
Vol 278 (6) ◽  
pp. H1966-H1973 ◽  
Author(s):  
H. T. Yang ◽  
Y. Feng ◽  
Laura A. Allen ◽  
Andrew Protter ◽  
Ronald L. Terjung
Keyword(s):  
Blood Flow ◽  
Vascular Occlusion ◽  
Treadmill Running ◽  
Collateral Flow ◽  
Collateral Blood Flow ◽  
Angiogenic Growth Factors ◽  
Short Term ◽  
Arterial Insufficiency ◽  
Peripheral Arterial ◽  
Calf Muscles

Angiogenic growth factors could prove to be useful in managing peripheral arterial insufficiency. The present study was designed to evaluate the dose response of basic fibroblast growth factor (bFGF), the efficacy of critical routes and dosing regimens, and the specificity of action in rats with peripheral arterial insufficiency. Bilateral ligation of femoral arteries greatly reduces blood flow capacity to the calf muscles but does not impair resting flow needs. Collateral blood flow to calf muscles was determined 16 days postocclusion, during treadmill running, with 85Sr and 141Ce microspheres, in blinded-randomized trials that included intra-arterial and intravenous infusions and subcutaneous injections of recombinant human bFGF. Peak blood flow of 75–80 ml ⋅ min− 1 ⋅ 100 g− 1 for calf muscle was observed at a bFGF dose of 5 μg ⋅ kg− 1 ⋅ day− 1(ia for 14 days) compared with 50 ml ⋅ min− 1 ⋅ 100 g− 1 for vehicle groups. Similar increases in collateral blood flow were observed with short-term or prolonged and continuous or intermittent delivery of bFGF by any route. Collateral blood flows were similar in corresponding muscles across both limbs. Vascular remodeling induced by bFGF required attendant vascular occlusion, inasmuch as vessels in the normal nonoccluded vascular tree were unresponsive to circulating bFGF. Improvement in collateral blood flow with exogenous bFGF is robust, amenable to short-term administration, and requires vascular occlusion to be effective.

Time course of changes in collateral blood flow and isolated vessel size and gene expression after femoral artery occlusion in rats

2004 ◽  
Vol 287 (6) ◽  
pp. H2434-H2447 ◽  
Author(s):  
Barry M. Prior ◽  
Pamela G. Lloyd ◽  
Jie Ren ◽  
Han Li ◽  
H. T. Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Blood Flow ◽  
Growth Factor ◽  
Time Course ◽  
Collateral Blood Flow ◽  
Collateral Vessel ◽  
Low Pressures ◽  
Over Time ◽  
Calf Muscles

The objectives of this study were to assess the time course of enlargement and gene expression of a collateral vessel that enlarges following occlusion of the femoral artery and to relate these responses to the increases in collateral-dependent blood flow to the calf muscles in vivo. We employed exercise training to stimulate collateral vessel development. Rats were exercise trained or kept sedentary for various times of up to 25 days postbilateral occlusion ( n = ∼9/time point). Collateral blood flow to the calf muscles, determined with microspheres, increased modestly over the first few days to ∼40 ml·min−1·100 g−1 in sedentary animals; the increase continued over time to ∼80 ml·min−1·100 g−1 in the trained animals. Diameters of the isolated collateral vessels increased progressively over time, whereas an increased vessel compliance observed at low pressures was similar across time. These responses were greater in the trained animals. The time course of upregulation of vascular endotheial growth factor and placental growth factor, and particularly endothelial nitric oxide synthase and fms-like tyrosine kinase 1, mRNAs in the isolated collateral vessel implicates these factors as integral to the arteriogenic process. Collateral vessel enlargement and increased compliance at low pressures contribute to the enlarged circuit available for collateral blood flow. However, modulation of the functioning collateral vessel diameter, by smooth muscle tone, must occur to account for the observed increases in collateral blood flow measured in vivo.

Exercise training enhances basic fibroblast growth factor-induced collateral blood flow

1998 ◽  
Vol 274 (6) ◽  
pp. H2053-H2061 ◽  
Author(s):  
H. T. Yang ◽  
Robert W. Ogilvie ◽  
Ronald L. Terjung
Keyword(s):  
Blood Flow ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Calf Muscle ◽  
Muscle Performance ◽  
Fibroblast Growth ◽  
Collateral Blood Flow ◽  
Collateral Vessel ◽  
Blood Flows

This study evaluated whether daily exercise would enhance the peripheral collateral vessel development found in response to exogenous basic fibroblast growth factor (bFGF) infusion. After bilateral femoral occlusion, male Sprague-Dawley rats (∼325 g) received intra-arterial infusions of either bFGF (1 μg/day; n = 15) or carrier solution ( n = 13) via osmotic pumps for 2 wk. Subgroups of each treatment were kept sedentary (cage activity) or trained by walking at 20 m/min at 15% grade, two times a day, 5 days/wk for 4 wk. Training markedly increased citrate synthase activity in the active muscle ( P < 0.001). Muscle function and blood flows (85Sr microsphere) were evaluated using an isolated hindquarter perfused at 100 mmHg via the abdominal aorta. The significant increase in blood flow to the entire hindlimb in the sedentary animals, caused by bFGF infusion ( P < 0.05), was further increased ( P < 0.01) in the bFGF-trained group. The quantitatively largest increases in blood flows were observed in the collateral-dependent tissues of the distal hindlimb. Blood flows to the entire calf muscle group increased ∼140% in carrier-trained ( P < 0.001), ∼180% in bFGF sedentary ( P< 0.001), and ∼240% in the bFGF-trained ( P < 0.001) groups compared with the carrier sedentary group. The increases in collateral blood flow were functionally important, as improvements in calf muscle performance correlated with measured blood flows. Our results demonstrate that exogenous bFGF administration in combination with a moderate-intensity exercise program greatly increases collateral-dependent blood flow and improves muscle performance. That physical activity enriched the bFGF response is consistent with the hypothesis that hemodynamic factors are important contributors to collateral vessel enlargement.

Role of Growth Factors in Improved Skin Flap Viability Caused by Phosphodiesterase-5 Inhibitor

2010 ◽  
Vol 76 (6) ◽  
pp. 614-617 ◽  
Author(s):  
Bradley C. Bandera ◽  
Thach Pham ◽  
Crystal Hill-Pryor ◽  
Mariama Bah-Sow ◽  
Nelson Franco ◽  
...  
Keyword(s):  
Blood Flow ◽  
Growth Factors ◽  
Growth Factor ◽  
Ribonucleic Acid ◽  
Skin Flap ◽  
Flap Necrosis ◽  
Angiogenic Growth Factors ◽  
Affected Area ◽  
Flap Viability ◽  
Phosphodiesterase 5

Flap necrosis is one of the major complications of reconstructive surgery and sildenafil citrate has been shown to decrease flap necrosis in preclinical animal models. However, the mechanisms underlying sildenafil's therapeutic efficacy are not known. As with other phosphodiesterase 5 selective inhibitors, sildenafil causes vasodilation and enhanced blood flow. In addition, sildenafil can also alter gene expression. This study is designed to test the hypothesis that increased expression of angiogenic growth factors may be responsible for therapeutic efficacy of sildenafil. A modified McFarlane flap measuring 3 X 10 cm was created on the dorsal skin of male Sprague-Dawley rats. For growth factor expression experiment, rats were administered either vehicle or sildenafil 10 mg/Kg intraperitoneal (IP). Ribonucleic acid (RNA) extracted from skin flap was analyzed to assess the messenger ribonucleic acid (mRNA) levels of different angiogenic growth factors. For skin flap viability experiment, fibrin film impregnated with vehicle, fibroblast growth factor (FGF) (5.0 μg) or vascular endothelial growth factor (VEGF) (2.0 μg) was applied to the wound. The skin flap was then returned to its native position and stapled in place. Total affected area (area of necrosis and blood flow stasis) of each rat on postoperative day 14 was analyzed with orthogonal polarization spectral imaging. Daily systemic treatment with sildenafil significantly ( P < 0.05) increased the expression of FGF1 and FGF Receptor 3 on postoperative day 3 by 5.08- and 4.78-fold, respectively. In addition, sildenafil increased the expression of VEGF-A, VEGF-B, and VEGF-C by 2.66-, 2.02-, and 2.00-fold, respectively. Subcutaneous treatment with FGF but not VEGF-A tended to decrease total affected area in rats. These data demonstrate that sildenafil altered the expression of FGF and VEGF. Altered expression of growth factors may be, at least partly, responsible for the beneficial effects of sildenafil citrate on skin viability.

Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases

2005 ◽  
Vol 289 (6) ◽  
pp. F1324-F1332 ◽  
Author(s):  
Manish M. Tiwari ◽  
Robert W. Brock ◽  
Judit K. Megyesi ◽  
Gur P. Kaushal ◽  
Philip R. Mayeux
Keyword(s):  
Nitric Oxide ◽  
Renal Failure ◽  
Blood Flow ◽  
Saline Group ◽  
No Production ◽  
Capillary Perfusion ◽  
Peritubular Capillary ◽  
Synthase Inhibitor ◽  
Peritubular Capillary Perfusion

Acute renal failure (ARF) is a frequent and serious complication of endotoxemia caused by lipopolysaccharide (LPS) and contributes significantly to mortality. The present studies were undertaken to examine the roles of nitric oxide (NO) and caspase activation on renal peritubular blood flow and apoptosis in a murine model of LPS-induced ARF. Male C57BL/6 mice treated with LPS ( Escherichia coli) at a dose of 10 mg/kg developed ARF at 18 h. Renal failure was associated with a significant decrease in peritubular capillary perfusion. Vessels with no flow increased from 7 ± 3% in the saline group to 30 ± 4% in the LPS group ( P < 0.01). Both the inducible NO synthase inhibitor l- N6-1-iminoethyl-lysine (l-NIL) and the nonselective caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (Z-VAD) prevented renal failure and reversed perfusion deficits. Renal failure was also associated with an increase in renal caspase-3 activity and an increase in renal apoptosis. Both l-NIL and Z-VAD prevented these changes. LPS caused an increase in NO production that was blocked by l-NIL but not by Z-VAD. Taken together, these data suggest NO-mediated activation of renal caspases and the resulting disruption in peritubular blood flow are an important mechanism of LPS-induced ARF.

Nitric oxide and cerebral blood flow responses to hyperbaric oxygen

2000 ◽  
Vol 88 (4) ◽  
pp. 1381-1389 ◽  
Author(s):  
Ivan T. Demchenko ◽  
Albert E. Boso ◽  
Thomas J. O'Neill ◽  
Peter B. Bennett ◽  
Claude A. Piantadosi
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Methyl Ester ◽  
No Production ◽  
No Donors ◽  
Mk 801 ◽  
Neuronal Excitation ◽  
Synthase Inhibitor ◽  
Electroencephalogram Eeg

We have tested the hypothesis that cerebral nitric oxide (NO) production is involved in hyperbaric O2 (HBO2) neurotoxicity. Regional cerebral blood flow (rCBF) and electroencephalogram (EEG) were measured in anesthetized rats during O2 exposure to 1, 3, 4, and 5 ATA with or without administration of the NO synthase inhibitor ( N ω-nitro-l-arginine methyl ester), l-arginine, NO donors, or the N-methyl-d-aspartate receptor inhibitor MK-801. After 30 min of O2 exposure at 3 and 4 ATA, rCBF decreased by 26–39% and by 37–43%, respectively, and was sustained for 75 min. At 5 ATA, rCBF decreased over 30 min in the substantia nigra by one-third but, thereafter, gradually returned to preexposure levels, preceding the onset of EEG spiking activity. Rats pretreated with N ω-nitro-l-arginine methyl ester and exposed to HBO2 at 5 ATA maintained a low rCBF. MK-801 did not alter the cerebrovascular responses to HBO2at 5 ATA but prevented the EEG spikes. NO donors increased rCBF in control rats but were ineffective during HBO2 exposures. The data provide evidence that relative lack of NO activity contributes to decreased rCBF under HBO2, but, as exposure time is prolonged, NO production increases and augments rCBF in anticipation of neuronal excitation.

scholarly journals The Antimicrobial Peptide Human β-Defensin-3 Accelerates Wound Healing by Promoting Angiogenesis, Cell Migration, and Proliferation Through the FGFR/JAK2/STAT3 Signaling Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Miho Takahashi ◽  
Yoshie Umehara ◽  
Hainan Yue ◽  
Juan Valentin Trujillo-Paez ◽  
Ge Peng ◽  
...  
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Growth Factors ◽  
Growth Factor ◽  
Antimicrobial Peptide ◽  
Fibroblast Growth Factor ◽  
Human Fibroblasts ◽  
Janus Kinase ◽  
Fibroblast Growth ◽  
Angiogenic Growth Factors

In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.

scholarly journals Nitric oxide production duringVibrio choleraeinfection

1997 ◽  
Vol 273 (5) ◽  
pp. G1160-G1167 ◽  
Author(s):  
Edward N. Janoff ◽  
Hiroshi Hayakawa ◽  
David N. Taylor ◽  
Claudine E. Fasching ◽  
Julie R. Kenner ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Epithelial Cells ◽  
Regional Blood Flow ◽  
Fluid Secretion ◽  
The United States ◽  
No Production ◽  
Loop Model ◽  
Ileal Loop

Vibrio cholerae induces massive intestinal fluid secretion that continues for the life of the stimulated epithelial cells. Enhanced regional blood flow and peristalsis are required to adapt to this obligatory intestinal secretory challenge. Nitric oxide (NO) is a multifunctional molecule that modulates blood flow and peristalsis and possesses both cytotoxic and antibacterial activity. We demonstrate that, compared with those in asymptomatic control subjects, levels of stable NO metabolites ([Formula: see text]/[Formula: see text]) are significantly increased in sera from acutely ill Peruvian patients with natural cholera infection as well as from symptomatic volunteers from the United States infected experimentally with V. cholerae. In a rabbit ileal loop model in vivo, cholera toxin (CT) elicited fluid secretion and dose-dependent increases in levels of[Formula: see text]/[Formula: see text]in the fluid ( P < 0.01). In contrast, lipopolysaccharide (LPS) elicited no such effects when applied to the intact mucosa. NO synthase (NOS) catalytic activity also increased in toxin-exposed tissues ( P< 0.05), predominantly in epithelial cells. The CT-induced NOS activity was Ca2+dependent and was not suppressed by dexamethasone. In conclusion, symptomatic V. cholerae infection induces NO production in humans. In the related animal model, CT, but not LPS, stimulated significant production of NO in association with increases in local Ca2+-dependent NOS activity in the tissues.

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