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1.
J Med Chem ; 61(21): 9691-9721, 2018 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-30289716

RESUMO

HIF-2α, a member of the HIF family of transcription factors, is a key oncogenic driver in cancers such as clear cell renal cell carcinoma (ccRCC). A signature feature of these cancers is the overaccumulation of HIF-2α protein, often by inactivation of the E3 ligase VHL (von Hippel-Lindau). Herein we disclose our structure based drug design (SBDD) approach that culminated in the identification of PT2385, the first HIF-2α antagonist to enter clinical trials. Highlights include the use of a putative n → π*Ar interaction to guide early analog design, the conformational restriction of an essential hydroxyl moiety, and the remarkable impact of fluorination near the hydroxyl group. Evaluation of select compounds from two structural classes in a sequence of PK/PD, efficacy, PK, and metabolite profiling identified 10i (PT2385, luciferase EC50 = 27 nM) as the clinical candidate. Finally, a retrospective crystallographic analysis describes the structural perturbations necessary for efficient antagonism.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/patologia , Desenho de Fármacos , Indanos/química , Indanos/farmacologia , Neoplasias Renais/patologia , Sulfonas/química , Sulfonas/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Linhagem Celular Tumoral , Cães , Indanos/farmacocinética , Camundongos , Modelos Moleculares , Conformação Proteica , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Distribuição Tecidual
2.
Cancer Res ; 76(18): 5491-500, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27635045

RESUMO

More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel-Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1ß. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491-500. ©2016 AACR.


Assuntos
Antineoplásicos/farmacologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Animais , Antineoplásicos/química , Calorimetria , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos SCID , Reação em Cadeia da Polimerase , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Neurotrauma ; 29(3): 579-88, 2012 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-21933012

RESUMO

Manipulation of various components of the endoplasmic reticulum (ER) stress response (ERSR) has led to functional recovery in diabetes, cancer, and several neurodegenerative diseases, indicating its use as a potential therapeutic intervention. One of the downstream pro-apoptotic transcription factors activated by the ERSR is CCAAT enhancer binding protein (C/EBP) homologous protein (CHOP). Recently, we showed significant recovery in hindlimb locomotion function after moderate contusive spinal cord injury (SCI) in mice null for CHOP. However, more than 40% of human SCI are complete. Thus the present study examined the potential therapeutic modulation of CHOP in a more severe SCI injury. Contused wild-type spinal cords showed a rapid activation of PERK, ATF6, and IRE-1, the three arms of the ERSR signaling pathway, specifically at the injury epicenter. Confocal images of phosphorylated EIF2α, GRP78, CHOP, ATF4, and GADD34 localized the activation of the ERSR in neurons and oligodendrocytes at the injury epicenter. To directly determine the role of CHOP, wild-type and CHOP-null mice with severe contusive SCI were analyzed for improvement in hindlimb locomotion. Despite the loss of CHOP, the other effectors in the ERSR pathway were significantly increased beyond that observed previously with moderate injury. Concomitantly, Basso Mouse Scale (BMS) scores and white matter sparing between the wild-type and CHOP-null mice revealed no significant differences. Given the complex pathophysiology of severe SCI, ablation of CHOP alone is not sufficient to rescue functional deficits. These data raise the caution that injury severity may be a key variable in attempting to translate preclinical therapies to clinical practice.


Assuntos
Apoptose/fisiologia , Retículo Endoplasmático/fisiologia , Locomoção/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Fator de Transcrição CHOP/fisiologia , Animais , Comportamento Animal/fisiologia , Western Blotting , Claudinas , Contusões/patologia , Contusões/fisiopatologia , Chaperona BiP do Retículo Endoplasmático , Feminino , Proteínas de Choque Térmico/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Básica da Mielina/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteína Fosfatase 1/metabolismo , RNA/biossíntese , RNA/isolamento & purificação , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia , Fator de Transcrição CHOP/genética
4.
Glia ; 59(10): 1489-502, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21638341

RESUMO

Activation of the unfolded protein response (UPR) is involved in the pathogenesis of numerous CNS myelin abnormalities; yet, its direct role in traumatic spinal cord injury (SCI)-induced demyelination is not known. The UPR is an evolutionarily conserved cell defense mechanism initiated to restore endoplasmic reticulum homeostasis in response to various cellular stresses including infection, trauma, and oxidative damage. However, if uncompensated, the UPR triggers apoptotic cell death. We demonstrate that the three signaling branches of UPR including the PERK, ATF6, and IRE1α are rapidly initiated in a mouse model of contusive SCI specifically at the injury epicenter. Immunohistochemical analyses of the various UPR markers revealed that in neurons, the UPR appeared at 6 and 24-h post-SCI. In contrast, in oligodendrocytes and astroglia, UPR persisted at least for up to 3 days post-SCI. The UPR-associated proapoptotic transcriptional regulator CHOP was among the UPR markers upregulated in neurons and oligodendrocytes, but not in astrocytes, of traumatized mouse spinal cords. To directly analyze its role in SCI, WT and CHOP null mice received a moderate T9 contusive injury. Deletion of CHOP led to an overall attenuation of the UPR after contusive SCI. Furthermore, analyses of hindlimb locomotion demonstrated a significant functional recovery that correlated with an increase in white-matter sparing, transcript levels of myelin basic protein, and Claudin 11 and decreased oligodendrocyte apoptosis in CHOP null mice in contrast to WT animals. Thus, our study provides evidence that the UPR contributes to oligodendrocyte loss after traumatic SCI.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Regulação para Cima/fisiologia , Fator 4 Ativador da Transcrição/metabolismo , Análise de Variância , Animais , Apoptose/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/genética , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Locomoção/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Fibras Nervosas Mielinizadas/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Fator de Transcrição 2 de Oligodendrócitos , Oligodendroglia/metabolismo , Oligodendroglia/patologia , RNA Mensageiro/metabolismo , Fatores de Transcrição de Fator Regulador X , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Fatores de Tempo , Fator de Transcrição CHOP/deficiência , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas/genética , Resposta a Proteínas não Dobradas/fisiologia , Regulação para Cima/genética
5.
Microcirculation ; 17(7): 557-67, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21040121

RESUMO

UNLABELLED: We have demonstrated that MFs isolated from adipose retain angiogenic potential in vitro and form a mature, perfused network when implanted. However, adipose-derived microvessels are rich in provascularizing cells that could uniquely drive neovascularization in adipose-derived MFs implants. OBJECTIVE: Investigate the ability of MFs from a different vascular bed to recapitulate adipose-derived microvessel angiogenesis and network formation and analyze adipose-derived vessel plasticity by assessing whether vessel function could be modulated by astrocyte-like cells. METHODS: MFs were isolated by limited collagenase digestion from rodent brain or adipose and assembled into 3D collagen gels in the presence or absence of GRPs. The resulting neovasculatures that formed following implantation were assessed by measuring 3D vascularity and vessel permeability to small and large molecular tracers. RESULTS: Similar to adipose-derived MFs, brain-derived MFs can sprout and form a perfused neovascular network when implanted. Furthermore, when co-implanted in the constructs, GRPs caused adipose-derived vessels to express the brain endothelial marker glucose transporter-1 and to significantly reduce microvessel permeability. CONCLUSION: Neovascularization involving isolated microvessel elements is independent of the tissue origin and degree of vessel specialization. In addition, adipose-derived vessels have the ability to respond to environmental signals and change vessel characteristics.


Assuntos
Microvasos/crescimento & desenvolvimento , Microvasos/transplante , Neovascularização Fisiológica , Adipócitos/citologia , Adipócitos/transplante , Animais , Astrócitos/citologia , Permeabilidade Capilar , Separação Celular , Córtex Cerebral/irrigação sanguínea , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/transplante , Epididimo/irrigação sanguínea , Epididimo/citologia , Técnicas In Vitro , Masculino , Microvasos/citologia , Microvasos/fisiologia , Neuroglia/citologia , Neuroglia/transplante , Ratos
6.
Brain ; 133(Pt 4): 1026-42, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20375135

RESUMO

Blood vessel loss and inflammation cause secondary degeneration following spinal cord injury. Angiopoietin-1 through the Tie2 receptor, and other ligands through alphavbeta3 integrin, promote endothelial cell survival during developmental or tumour angiogenesis. Here, daily intravenous injections with an alphavbeta3-binding peptide named C16 or an angiopoietin-1 mimetic following a spinal cord contusion at thoracic level 9 in mice rescued epicentre blood vessels, white matter and locomotor function, and reduced detrimental inflammation. Preserved vascularity and reduced inflammation correlated with improved outcomes. C16 and angiopoietin-1 reduced leukocyte transmigration in vitro. Growth factor receptors and integrins facilitate each others' function. Therefore, angiopoietin-1 and C16 were combined and the effects were additive, resulting in almost complete functional recovery. The treatment had lasting effects when started 4 h following injury and terminated after one week. These results identify alphavbeta3 integrin and the endothelial-selective angiopoietin-1 as vascular and inflammatory regulators that can be targeted in a clinically relevant manner for neuroprotection after central nervous system trauma.


Assuntos
Angiopoietina-1/administração & dosagem , Integrina alfaVbeta3/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Fragmentos de Peptídeos/administração & dosagem , Traumatismos da Medula Espinal/prevenção & controle , Medula Espinal/irrigação sanguínea , Medula Espinal/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Quimioterapia Combinada , Feminino , Humanos , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Vértebras Torácicas , Fatores de Tempo
7.
ASN Neuro ; 1(3)2009 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-19663807

RESUMO

Microvascular dysfunction, loss of vascular support, ischaemia and sub-acute vascular instability in surviving blood vessels contribute to secondary injury following SCI (spinal cord injury). Neither the precise temporal profile of the cellular dynamics of spinal microvasculature nor the potential molecular effectors regulating this plasticity are well understood. TGFß (transforming growth factor ß) isoforms have been shown to be rapidly increased in response to SCI and CNS (central nervous system) ischaemia, but no data exist regarding their contribution to microvascular dysfunction following SCI. To examine these issues, in the present study we used a model of focal spinal cord ischaemia/reperfusion SCI to examine the cellular response(s) of affected microvessels from 30 min to 14 days post-ischaemia. Spinal endothelial cells were isolated from affected tissue and subjected to focused microarray analysis of TGFß-responsive/related mRNAs 6 and 24 h post-SCI. Immunohistochemical analyses of histopathology show neuronal disruption/loss and astroglial regression from spinal microvessels by 3 h post-ischaemia, with complete dissolution of functional endfeet (loss of aquaporin-4) by 12 h post-ischaemia. Coincident with this microvascular plasticity, results from microarray analyses show 9 out of 22 TGFß-responsive mRNAs significantly up-regulated by 6 h post-ischaemia. Of these, serpine 1/PAI-1 (plasminogen-activator inhibitor 1) demonstrated the greatest increase (>40-fold). Furthermore, uPA (urokinase-type plasminogen activator), another member of the PAS (plasminogen activator system), was also significantly increased (>7.5-fold). These results, along with other select up-regulated mRNAs, were confirmed biochemically or immunohistochemically. Taken together, these results implicate TGFß as a potential molecular effector of the anatomical and functional plasticity of microvessels following SCI.


Assuntos
Células Endoteliais/metabolismo , Microvasos/fisiologia , Traumatismo por Reperfusão/metabolismo , Isquemia do Cordão Espinal/metabolismo , Ativação Transcricional/fisiologia , Fator de Crescimento Transformador beta/biossíntese , Animais , Células Endoteliais/patologia , Feminino , Microvasos/patologia , Plasticidade Neuronal/fisiologia , RNA Mensageiro/biossíntese , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/patologia , Isquemia do Cordão Espinal/patologia
8.
Curr Neurovasc Res ; 6(2): 124-31, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19442162

RESUMO

Acute loss of spinal cord vascularity followed by an endogenous adaptive angiogenic response with concomitant microvascular dysfunction is a hallmark of traumatic spinal cord injury (SCI). Recently, the potent vasoactive factor vascular endothelial growth factor (VEGF) has received much attention as a putative therapeutic for the treatment of various neurodegenerative disorders, including SCI. Exogenous VEGF exerts both protective and destabilizing effects on microvascular elements and tissue following SCI but the role of endogenous VEGF is unclear. In the present study, we systemically applied a potent and well characterized soluble VEGF antagonist to adult C57Bl/6 mice post-SCI to elucidate the relative contribution of VEGF on the acute evolving microvascular response and its impact on functional recovery. While the VEGF Trap did not alter vascular density in the injury epicenter or penumbra, an overall increase in the number of Griffonia simplicifolia isolectin-B4 bound microvessels was observed, suggesting a VEGF-dependency to more subtle aspects of endothelial plasticity post-SCI. Neutralizing endogenous VEGF neither attenuated nor exacerbated chronic histopathology or functional recovery. These results support the idea that overall, endogenous VEGF is not neuroprotective or detrimental following traumatic SCI. Furthermore, they suggest that angiogenesis in traumatically injured spinal tissue is regulated by multiple effectors and is not limited by endogenous VEGF activation of affected spinal microvessels.


Assuntos
Microvasos/efeitos dos fármacos , Regeneração Nervosa/efeitos dos fármacos , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Análise de Variância , Animais , Modelos Animais de Doenças , Feminino , Imunoglobulina G/uso terapêutico , Lectinas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microvasos/patologia , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/uso terapêutico , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/tratamento farmacológico , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/uso terapêutico
9.
J Comp Neurol ; 512(2): 243-55, 2009 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-19003792

RESUMO

Endothelial cell (EC) loss and subsequent angiogenesis occur over the first week after spinal cord injury (SCI). To identify molecular mechanisms that could be targeted with intravenous (i.v.) treatments, we determined whether transmembrane "a disintegrin and metalloprotease" (ADAM) proteins are expressed in ECs of the injured spinal cord. ADAMs bind to integrins, which are important for EC survival and angiogenesis. Female adult C57Bl/6 mice with a spinal cord contusion had progressively more ADAM8 (CD156) immunostaining in blood vessels and individual ECs between 1 and 28 days following injury. Uninjured spinal cords had little ADAM8 staining. The increase in ADAM8 mRNA and protein was confirmed in spinal cord lysates, and ADAM8 mRNA was present in FACS-enriched ECs. ADAM8 colocalized extensively and exclusively with the EC marker PECAM and also with i.v.-injected lectins. Intravenous isolectin B4 (IB4) labels a subpopulation of blood vessels at and within the injury epicenter 3-7 days after injury, coincident with angiogenesis. Both ADAM8 and the proliferation marker Ki-67 were present in IB4-positive microvessels. ADAM8-positive proliferating cells were seen at the leading end of IB4-positive blood vessels. Angiogenesis was confirmed by BrdU incorporation, binding of i.v.-injected nucleolin antibodies, and MT1-MMP immunostaining in a subset of blood vessels. These data suggest that ADAM8 is vascular selective and plays a role in proliferation and/or migration of ECs during angiogenesis following SCI.


Assuntos
Proteínas ADAM/metabolismo , Antígenos CD/metabolismo , Células Endoteliais/metabolismo , Proteínas de Membrana/metabolismo , Neovascularização Fisiológica/fisiologia , Traumatismos da Medula Espinal/metabolismo , Adulto , Animais , Biomarcadores/metabolismo , Vasos Sanguíneos/anatomia & histologia , Vasos Sanguíneos/metabolismo , Células Endoteliais/citologia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Medula Espinal/citologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologia
10.
J Cereb Blood Flow Metab ; 28(11): 1771-85, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18612314

RESUMO

Microvascular dysfunction is a critical pathology that underlies the evolution of secondary injury mechanisms after traumatic spinal cord injury (SCI). However, little is known of the molecular regulation of endothelial cell (EC) plasticity observed acutely after injury. One reason for this is the relative lack of methods to quickly and efficiently obtain highly enriched spinal microvascular ECs for high-throughput molecular and biochemical analyses. Adult C57Bl/6 mice received an intravenous injection of fluorescein isothiocyanate (FITC)-conjugated Lycopersicon esculentum lectin, and FITC-lectin-bound spinal microvessels were greatly enriched by fluorescence-activated cell sorter (FACS) purification. This technique allows for rapid (<1.5 h postmortem) isolation of spinal cord microvascular ECs (smvECs). The results from cell counting, reverse-transcription polymerase chain reaction (RT-PCR), and western blot analyses show a high degree of EC enrichment at mRNA and protein levels. Furthermore, a focused EC biology microarray analysis identified multiple mRNAs dramatically increased in the EC compartment 24 h after SCI, which is a time point associated with the pathologic loss of spinal vasculature. These included thrombospondin-1, CCL5/RANTES, and urokinase plasminogen activator, suggesting they may represent targets for therapeutic intervention. Furthermore, these novel methodologic approaches will likely facilitate the discovery of molecular regulators of endothelial dysfunction in a variety of central nervous system (CNS) disorders including stroke and other neurodegenerative diseases having a vascular component.


Assuntos
Endotélio Vascular/fisiopatologia , Perfilação da Expressão Gênica , Microcirculação/fisiologia , RNA Mensageiro/genética , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/irrigação sanguínea , Transcrição Gênica , Animais , Anexinas/genética , Endotélio Vascular/patologia , Feminino , Fibrinolisina/genética , Citometria de Fluxo , Regulação da Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microcirculação/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Lectinas de Plantas , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trombospondinas/genética , Ativador de Plasminogênio Tipo Uroquinase/genética
11.
J Comp Neurol ; 507(1): 1031-52, 2008 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-18092342

RESUMO

After traumatic spinal cord injury (SCI), disruption and plasticity of the microvasculature within injured spinal tissue contribute to the pathological cascades associated with the evolution of both primary and secondary injury. Conversely, preserved vascular function most likely results in tissue sparing and subsequent functional recovery. It has been difficult to identify subclasses of damaged or regenerating blood vessels at the cellular level. Here, adult mice received a single intravenous injection of the Griffonia simplicifolia isolectin B4 (IB4) at 1-28 days following a moderate thoracic (T9) contusion. Vascular binding of IB4 was maximally observed 7 days following injury, a time associated with multiple pathologic aspects of the intrinsic adaptive angiogenesis, with numbers of IB4 vascular profiles decreasing by 21 days postinjury. Quantitative assessment of IB4 binding shows that it occurs within the evolving lesion epicenter, with affected vessels expressing a temporally specific dysfunctional tight junctional phenotype as assessed by occludin, claudin-5, and ZO-1 immunoreactivities. Taken together, these results demonstrate that intravascular lectin delivery following SCI is a useful approach not only for observing the functional status of neovascular formation but also for definitively identifying specific subpopulations of reactive spinal microvascular elements.


Assuntos
Camundongos Endogâmicos C57BL/fisiologia , Neovascularização Fisiológica/fisiologia , Lectinas de Plantas , Traumatismos da Medula Espinal/fisiopatologia , Coluna Vertebral/irrigação sanguínea , Adaptação Fisiológica/fisiologia , Fatores Etários , Animais , Capilares/citologia , Capilares/fisiologia , Capilares/ultraestrutura , Divisão Celular/fisiologia , Endotélio Vascular/citologia , Endotélio Vascular/fisiologia , Endotélio Vascular/ultraestrutura , Feminino , Camundongos , Microscopia Imunoeletrônica , Traumatismos da Medula Espinal/patologia , Coluna Vertebral/patologia , Junções Íntimas/fisiologia
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