Early Vessel Destabilization Mediated by Angiopoietin-2 and Subsequent Vessel Maturation via Angiopoietin-1 Induce Functional Neovasculature after Ischemia

Qin, Di; Trenkwalder, Teresa; Lee, Seungmin; Chillo, Omary; Deindl, Elisabeth; Kupatt, Christian; Hinkel, Rabea

doi:10.1371/journal.pone.0061831

Cited by 41 publications

(47 citation statements)

References 31 publications

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“…The expansion of the renal microvasculature was accompanied and likely mediated by the distinct increased expression of VEGF and the Flk-1 receptor, Ang-1 (which may have improved the maturation and accelerated the functionality of the newly generated vessels 25 ), Ang-2 (which is proangiogenic when tissue levels of VEGF are high 26 ), and the Tie-2 receptor, and augmented p-Akt. 27 These are all crucial downstream effectors of the VEGF-mediated angiogenic cascade and suggest a potential restoration of proangiogenic activity.…”

Section: Discussionmentioning

confidence: 99%

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

Chade¹,

Tullos²,

Harvey³

et al. 2015

JASN

104

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Renovascular disease (RVD) induces renal microvascular (MV) rarefaction that drives progressive kidney injury. In previous studies, we showed that renal vascular endothelial growth factor (VEGF) therapy attenuated MV damage, but did not resolve renal injury at practical clinical doses. To increase the bioavailability of VEGF, we developed a biopolymer-stabilized elastin-like polypeptide (ELP)-VEGF fusion protein and determined its in vivo potential for therapeutic renal angiogenesis in RVD using an established swine model of chronic RVD. We measured single-kidney blood flow (RBF) and GFR and established the degree of renal damage after 6 weeks of RVD. Pigs then received a single stenotic kidney infusion of ELP-VEGF (100 mg/kg), a matching concentration of unconjugated VEGF (18.65 mg/kg), ELP alone (100 mg/kg), or placebo. Analysis of organ distribution showed high renal binding of ELP-VEGF 4 hours after stenotic kidney infusion. Therapeutic efficacy was determined 4 weeks after infusion. ELP-VEGF therapy improved renal protein expression attenuated in RVD, restoring expression levels of VEGF, VEGF receptor Flk-1, and downstream angiogenic mediators, including phosphorylated Akt and angiopoietin-1 and -2. This effect was accompanied by restored MV density, attenuated fibrogenic activity, and improvements in RBF and GFR greater than those observed with placebo, ELP alone, or unconjugated VEGF. In summary, we demonstrated the feasibility of a novel therapy to curtail renal injury. Recovery of the stenotic kidney in RVD after ELP-VEGF therapy may be driven by restoration of renal angiogenic signaling and attenuated fibrogenic activity, which ameliorates MV rarefaction and improves renal function. 27: 174127: -175227: , 201627: . doi: 10.1681 Renal vascular disease (RVD), usually caused by renal artery stenosis, can lead to CKD and ESRD. RVD increases cardiovascular morbidity and mortality, hospitalization, shortens life expectancy, and is increasing at a sustained pace in the United States. 1 Moreover, renal function does not improve or even deteriorates in almost half of the patients with RVD despite treatment. Recent clinical studies suggest that patients undergoing current therapeutic strategies, which include drugs and renal angioplasty, do not show differences in outcomes that could demonstrate distinct benefits of one treatment over the other when compared side by side. 2,3 Moreover, renal function does not improve or even deteriorates in almost half of patients with RVD despite treatment, highlighting a pressing need for novel therapeutic strategies for the growing population of patients suffering from RVD. J Am Soc NephrolUsing a clinically relevant swine model of chronic RVD that mimics several of the pathologic features

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Section: Discussionmentioning

confidence: 99%

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

Chade¹,

Tullos²,

Harvey³

et al. 2015

JASN

104

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“…ANG‐2 and PLGF were found to be the most abundantly secreted angiogenic growth factors, independent of underlying ischemic disease. Both ANG‐2 and PLGF play an important role in the complex cytokine cocktail, mediating the overall neovascularization process in ischemic disease 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47…”

Section: Discussionmentioning

confidence: 99%

Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

Dauwe

Pelacho

Wibowo

et al. 2016

JAHA

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BackgroundBlood outgrowth endothelial cells (BOECs) mediate therapeutic neovascularization in experimental models, but outgrowth characteristics and functionality of BOECs from patients with ischemic cardiomyopathy (ICMP) are unknown. We compared outgrowth efficiency and in vitro and in vivo functionality of BOECs derived from ICMP with BOECs from age‐matched (ACON) and healthy young (CON) controls.Methods and ResultsWe isolated 3.6±0.6 BOEC colonies/100×106 mononuclear cells (MNCs) from 60‐mL blood samples of ICMP patients (n=45; age: 66±1 years; LVEF: 31±2%) versus 3.5±0.9 colonies/100×106 MNCs in ACON (n=32; age: 60±1 years) and 2.6±0.4 colonies/100×106 MNCs in CON (n=55; age: 34±1 years), P=0.29. Endothelial lineage (VEGFR2+/CD31+/CD146+) and progenitor (CD34+/CD133−) marker expression was comparable in ICMP and CON. Growth kinetics were similar between groups (P=0.38) and not affected by left ventricular systolic dysfunction, maladaptive remodeling, or presence of cardiovascular risk factors in ICMP patients. In vitro neovascularization potential, assessed by network remodeling on Matrigel and three‐dimensional spheroid sprouting, did not differ in ICMP from (A)CON. Secretome analysis showed a marked proangiogenic profile, with highest release of angiopoietin‐2 (1.4±0.3×105 pg/106 ICMP‐BOECs) and placental growth factor (5.8±1.5×103 pg/106 ICMP BOECs), independent of age or ischemic disease. Senescence‐associated β‐galactosidase staining showed comparable senescence in BOECs from ICMP (5.8±2.1%; n=17), ACON (3.9±1.1%; n=7), and CON (9.0±2.8%; n=13), P=0.19. High‐resolution microcomputed tomography analysis in the ischemic hindlimb of nude mice confirmed increased arteriogenesis in the thigh region after intramuscular injections of BOECs from ICMP (P=0.025; n=8) and CON (P=0.048; n=5) over vehicle control (n=8), both to a similar extent (P=0.831).Conclusions BOECs can be successfully culture‐expanded from patients with ICMP. In contrast to impaired functionality of ICMP‐derived bone marrow MNCs, BOECs retain a robust proangiogenic profile, both in vitro and in vivo, with therapeutic potential for targeting ischemic disease.

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“…Before induction of ischaemia (day À 14), 3 Â 10 12 rAAV virus particles were applied intramuscularly to the right leg as indicated 46 . On day 0 the left leg underwent sham operation, whereas the femoral artery was ligated in the right leg.…”

Section: Methodsmentioning

confidence: 99%

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

et al. 2014

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Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin 4 (T 4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or T 4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the T 4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as T 4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing T 4 (T 4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.

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Early Vessel Destabilization Mediated by Angiopoietin-2 and Subsequent Vessel Maturation via Angiopoietin-1 Induce Functional Neovasculature after Ischemia

Cited by 41 publications

References 31 publications

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

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