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Biomedical subjects

Donald M McDonald

Publications and source records attributed to Donald M McDonald.

At least 19 recordsLinked to original sources

Cell labeling with the positive MR contrast agent Gadofluorine M.

The purpose of this study was to label human monocytes with Gadofluorine M by simple incubation for subsequent cell depiction at 1.5 and 3 T. Gadofluorine M displays a high r(1) relaxivity and is spontaneously phagocytosed by macrophages. Human monocytes were incubated with Gadofluorine M-Cy at varying concentrations and incubation times and underwent MR imaging at 1.5 and 3 T at increasing time intervals after the labeling procedure. R1-relaxation rates and r1 relaxivities of the labeled cells and non-labeled controls were determined. Cellular contrast agent uptake was examined by fluorescence microscopy and quantified by ICP-AES. Efficient cell labeling was achieved after incubation of the cells with 25 mM Gd Gadofluorine M for 12 h, resulting in a maximal uptake of 0.3 fmol Gd/cell without impairment of cell viability. Fluorescence microscopy confirmed internalization of the fluorescent contrast agent by monocytes. The r1 relaxivity of the labeled cells was 137 mM(-1)s(-1) at 1.5 T and 80.46 mM(-1)s(-1) at 3 T. Imaging studies showed stable labeling for at least 7 days. Human monocytes can be effectively labeled for MR imaging with Gadofluorine M. Potential in vivo cell-tracking applications include targeting of inflammatory processes with Gadofluorine-labeled leukocytes or monitoring of stem cell therapies for the treatment of arthritis.

Cells, Cultured↗

In vivo actions of angiopoietins on quiescent and remodeling blood and lymphatic vessels in mouse airways and skin.

OBJECTIVE: We investigated and compared the in vivo effects of all four angiopoietins (COMP-Ang1, Ang2, Ang3, and Ang4) on blood and lymphatic vascular remodeling in adult mice. We analyzed the microvasculature of trachea and ear skin, and compared quiescent skin microvasculature with that during wound healing. METHODS AND RESULTS: We were able to achieve similar levels of relatively long-term and sustained circulating expression of each angiopoietin using an adenoviral delivery system. Two weeks after treatment, we observed tracheal blood and lymphatic vascular enlargement, and lymphatic filopodia formation, with the following order of potency: COMP-Ang1>Ang3=Ang4>Ang2. Co-treatment with Ang2 attenuated Ang1-induced tracheal blood and lymphatic remodeling. In the normal ear skin, all angiopoietins induced blood vessel enlargement, whereas none induced lymphatic vascular remodeling. However, in the healing margin of ear skin wounds, all angiopoietins strongly induced lymphatic vascular enlargement and formation of lymphatic sprouts and filopodia, while they potentiated blood vascular enlargement. Co-treatment of Ang2 with Ang1 produced an additive effect on these changes. CONCLUSION: This study, one of the first to our knowledge to characterize the in vivo actions of all 4 angiopoietins, may expand the current concepts for use of angiopoietins for therapeutic angiogenesis and lymphangiogenesis.

Angiopoietins↗

Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells.

Angiopoietin (Ang)-2, a context-dependent agonist/antagonist for the vascular-specific Tie2 receptor, is highly expressed by endothelial cells at sites of normal and pathologic angiogenesis. One prevailing model suggests that in these settings, Ang-2 acts as an autocrine Tie2 blocker, inhibiting the stabilizing influence of the Tie2 activator Ang-1, thereby promoting vascular remodeling. However, the effects of endogenous Ang-2 on cells that are actively producing it have not been studied in detail. Here, we demonstrate that Ang-2 expression is rapidly induced in endothelial cells by the transcription factor FOXO1 after inhibition of the phosphatidylinositol 3-kinase/Akt pathway. We employ RNAi and blocking antibodies to show that in this setting, Ang-2 unexpectedly functions as a Tie2 agonist, bolstering Akt activity so as to provide negative feedback on FOXO1-regulated transcription and apoptosis. In addition, we show that Ang-2, like Ang-1, activates Tie2/Akt signaling in vivo, thereby inhibiting the expression of FOXO1 target genes. Consistent with a role for Ang-2 as a Tie2 activator, we demonstrate that Ang-2 inhibits vascular leak. Our data suggests a model in which Ang-2 expression is induced in stressed endothelial cells, where it acts as an autocrine Tie2 agonist and protective factor.

Androstadienes↗

Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung.

VEGF, nitric oxide (NO), inflammation, and vascular- and extravascular remodeling coexist in asthma and other disorders. In these responses, VEGF regulates angiogenesis. VEGF also induces inflammation and remodeling. The mechanisms of the latter responses have not been defined, however. We hypothesized that VEGF-induces extravascular tissue responses via NO-dependent mechanisms. To evaluate this hypothesis, we compared the effects of transgenic VEGF165 in lungs from normal mice, mice treated with pan-NO synthase (NOS) or endothelial NOS (eNOS) inhibitors, and mice with null mutations of inducible NOS (iNOS) or eNOS. These studies demonstrate that VEGF selectively stimulates eNOS and iNOS. They also demonstrate that VEGF induces pulmonary alterations via NO-dependent and -independent mechanisms with angiogenesis, edema, mucus metaplasia, airway hyperresponsiveness, lymphocyte accumulation, dendritic cell hyperplasia and S-nitrosoglutathione reductase stimulation being NO-dependent and dendritic cell activation being NO-independent. Furthermore, they demonstrate that eNOS and iNOS both contribute to these responses. NO/NOS-based interventions may be therapeutic in VEGF-driven inflammation and remodeling.

Alcohol Dehydrogenase↗

Antiangiogenic therapy decreases integrin expression in normalized tumor blood vessels.

Tumor blood vessels normalized by antiangiogenic therapy may provide improved delivery of chemotherapeutic agents during a window of time but it is unknown how protein expression in tumor vascular endothelial cells changes. We evaluated the distribution of RGD-4C phage, which binds alpha(v)beta(3), alpha(v)beta(5), and alpha(5)beta(1) integrins on tumor blood vessels before and after antiangiogenic therapy. Unlike the control phage, fd-tet, RGD-4C phage homed to vascular endothelial cells in spontaneous tumors in RIP-Tag2 transgenic mice in a dose-dependent fashion. The distribution of phage was similar to alpha(v)beta(3) and alpha(5)beta(1) integrin expression. Blood vessels that survived treatment with AG-013736, a small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, had only 4% as much binding of RGD-4C phage compared with vessels in untreated tumors. Cellular distribution of RGD-4C phage in surviving tumor vessels matched the alpha(5)beta(1) integrin expression. The reduction in integrin expression on tumor vessels after antiangiogenic therapy raises the possibility that integrin-targeted delivery of diagnostics or therapeutics may be compromised. Efficacious delivery of drugs may benefit from identification by in vivo phage display of targeting peptides that bind to tumor blood vessels normalized by antiangiogenic agents.

Adenoma, Islet Cell↗

Effect of inhibition of vascular endothelial growth factor signaling on distribution of extravasated antibodies in tumors.

Antibodies and other macromolecular therapeutics can gain access to tumor cells via leaky tumor vessels. Inhibition of vascular endothelial growth factor (VEGF) signaling can reduce the vascularity of tumors and leakiness of surviving vessels, but little is known about how these changes affect the distribution of antibodies within tumors. We addressed this issue by examining the distribution of extravasated antibodies in islet cell tumors of RIP-Tag2 transgenic mice and implanted Lewis lung carcinomas using fluorescence and confocal microscopic imaging. Extravasated nonspecific immunoglobulin G (IgG) and antibodies to fibrin or E-cadherin accumulated in irregular patchy regions of stroma. Fibrin also accumulated in these regions. Anti-E-cadherin antibody, which targets epitopes on tumor cells of RIP-Tag2 adenomas, was the only antibody to achieve detectable levels within tumor cell clusters at 6 hours after i.v. injection. Treatment for 7 days with AG-013736, a potent inhibitor of VEGF signaling, reduced the tumor vascularity by 86%. The overall area density of extravasated IgG/antibodies decreased after treatment but the change was less than the reduction in vascularity and actually increased when expressed per surviving tumor vessel. Accumulation of anti-E-cadherin antibody in tumor cell clusters was similarly affected. The patchy pattern of antibodies in stroma after treatment qualitatively resembled untreated tumors and surprisingly coincided with sleeves of basement membrane left behind after pruning of tumor vessels. Together, the findings suggest that antibody transport increases from surviving tumor vessels after normalization by inhibition of VEGF signaling. Basement membrane sleeves may facilitate this transport. Antibodies preferentially distribute to tumor stroma but also accumulate on tumor cells if binding sites are accessible.

Adenoma, Islet Cell↗

Rapid vascular regrowth in tumors after reversal of VEGF inhibition.

Inhibitors of VEGF signaling can block angiogenesis and reduce tumor vascularity, but little is known about the reversibility of these changes after treatment ends. In the present study, regrowth of blood vessels in spontaneous RIP-Tag2 tumors and implanted Lewis lung carcinomas in mice was assessed after inhibition of VEGF receptor signaling by AG-013736 or AG-028262 for 7 days. Both agents caused loss of 50%-60% of tumor vasculature. Empty sleeves of basement membrane were left behind. Pericytes also survived but had less alpha-SMA immunoreactivity. One day after drug withdrawal, endothelial sprouts grew into empty sleeves of basement membrane. Vessel patency and connection to the bloodstream followed close behind. By 7 days, tumors were fully revascularized, and the pericyte phenotype returned to baseline. Importantly, the regrown vasculature regressed as much during a second treatment as it did in the first. Inhibition of MMPs or targeting of type IV collagen cryptic sites by antibody HUIV26 did not eliminate the sleeves or slow revascularization. These results suggest that empty sleeves of basement membrane and accompanying pericytes provide a scaffold for rapid revascularization of tumors after removal of anti-VEGF therapy and highlight their importance as potential targets in cancer therapy.

Actins↗

Angiogenesis with pericyte abnormalities in a transgenic model of prostate carcinoma.

BACKGROUND: Previous studies of the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model vasculature suggest that, as tumors develop, vessels invade the glandular epithelium. However, changes in the vasculature are difficult to study in conventional thin tissue sections. The authors used a new approach to characterize morphologic and architectural changes of blood vessels and pericytes during tumor development in TRAMP mice. METHODS: Eighty-micron cryostat sections of normal prostate and three histopathologic stages of TRAMP tumor sections, classified by epithelial cell E-cadherin immunoreactivity, were immunostained with vascular endothelial cell and pericyte receptor antibodies and evaluated by confocal microscopy. RESULTS: In the normal mouse prostate, capillaries were most abundant in the fibromuscular tunica between the epithelium and smooth muscle of the ductules. In the prostatic intraepithelial neoplasia (PIN) stage, vessels accompanied epithelial cell protrusions into the ductule lumen but remained in the connective tissue at the basal side of the epithelium. Well differentiated tissues had extensive angiogenesis with five times the normal mean vascularity outside ductules. Vessels were of variable diameter, were associated with an increased number of pericytes, and some had endothelial sprouts. Angiogenic blood vessels from poorly differentiated adenocarcinomas were tortuous, variable in caliber, and lacked the normal hierarchy. Pericytes on these vessels had an abnormal phenotype manifested by alpha-smooth muscle actin expression and loose association with endothelial cells. Angiogenesis and loss of vascular hierarchy were also found in human prostate carcinoma. CONCLUSIONS: Vascular abnormalities, which begin at the PIN stage and intensify in well differentiated and poorly differentiated tumors, may be useful readouts for early detection and treatment assessment in prostate carcinoma.

Adenocarcinoma↗

Immune complex-dependent remodeling of the airway vasculature in response to a chronic bacterial infection.

Chronic inflammation in the airways is associated with dramatic architectural changes in the walls of the airways and in the vasculature they contain. In this study, we show that the adaptive immune system is essential for airway remodeling that occurs in mice that are chronically infected with the respiratory pathogen Mycoplasma pulmonis. Angiogenesis, lymphangiogenesis, and epithelial remodeling were greatly reduced in mice that lacked B cells. Substantiating a role for Ab and airway immune complexes, we found that the transfer of immune serum to B cell-deficient mice could reconstitute pathogen-induced angiogenesis. Inflammatory cells recruited to the infected airways were activated by the humoral response, and this activation correlated with the induction of genes for remodeling factors such as vascular endothelial growth factor-D. The results reveal a novel pathway whereby T cell-dependent humoral immunity to a persistent airway infection can induce inflammation-dependent angiogenesis, lymphangiogenesis, and chronic airway pathology.

Animals↗

Mast cells protect mice from Mycoplasma pneumonia.

RATIONALE: As the smallest free-living bacteria and a frequent cause of respiratory infections, mycoplasmas are unique pathogens. Mice infected with Mycoplasma pulmonis can develop localized, life-long airway infection accompanied by persistent inflammation and remodeling. OBJECTIVE: Because mast cells protect mice from acute septic peritonitis and gram-negative pneumonia, we hypothesized that they defend against mycoplasma infection. This study tests this hypothesis using mast cell-deficient mice. METHODS: Responses to airway infection with M. pulmonis were compared in wild-type and mast cell-deficient Kit(W-sh)/Kit(W-sh) mice and sham-infected control mice. MEASUREMENTS AND MAIN RESULTS: Endpoints include mortality, body and lymph node weight, mycoplasma antibody titer, and lung mycoplasma burden and histopathology at intervals after infection. The results reveal that infected Kit(W-sh)/Kit(W-sh) mice, compared with other groups, lose more weight and are more likely to die. Live mycoplasma burden is greater in Kit(W-sh)/Kit(W-sh) than in wild-type mice at early time points. Four days after infection, the difference is 162-fold. Titers of mycoplasma-specific IgM and IgA appear earlier and rise higher in Kit(W-sh)/Kit(W-sh) mice, but antibody responses to heat-killed mycoplasma are not different compared with wild-type mice. Infected Kit(W-sh)/Kit(W-sh) mice develop larger bronchial lymph nodes and progressive pneumonia and airway occlusion with neutrophil-rich exudates, accompanied by angiogenesis and lymphangiogenesis. In wild-type mice, pneumonia and exudates are less severe, quicker to resolve, and are not associated with increased angiogenesis. CONCLUSIONS: These findings suggest that mast cells are important for innate immune containment of and recovery from respiratory mycoplasma infection.

Animals↗

VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.

Unlike during development, blood vessels in the adult are generally thought not to require VEGF for normal function. However, VEGF is a survival factor for many tumor vessels, and there are clues that some normal blood vessels may also depend on VEGF. In this study, we sought to identify which, if any, vascular beds in adult mice depend on VEGF for survival. Mice were treated with a small-molecule VEGF receptor (VEGFR) tyrosine kinase inhibitor or soluble VEGFRs for 1-3 wk. Blood vessels were assessed using immunohistochemistry or scanning or transmission electron microscopy. In a study of 17 normal organs after VEGF inhibition, we found significant capillary regression in pancreatic islets, thyroid, adrenal cortex, pituitary, choroid plexus, small-intestinal villi, and epididymal adipose tissue. The amount of regression was dose dependent and varied from organ to organ, with a maximum of 68% in thyroid, but was less in normal organs than in tumors in RIP-Tag2-transgenic mice or in Lewis lung carcinoma. VEGF-dependent capillaries were fenestrated, expressed high levels of both VEGFR-2 and VEGFR-3, and had normal pericyte coverage. Surviving capillaries in affected organs had fewer fenestrations and less VEGFR expression. All mice appeared healthy, but distinct physiological changes, including more efficient blood glucose handling, accompanied some regimens of VEGF inhibition. Strikingly, most capillaries in the thyroid grew back within 2 wk after cessation of treatment for 1 wk. Our findings of VEGF dependency of normal fenestrated capillaries and rapid regrowth after regression demonstrate the plasticity of the adult microvasculature.

Aging↗

Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling.

The vasculature of the embryo requires vascular endothelial growth factor (VEGF) during development, but most adult blood vessels lose VEGF dependence. However, some capillaries in the respiratory tract and selected other organs of adult mice regress after VEGF inhibition. The present study sought to identify the sequence of events and the fate of endothelial cells, pericytes, and vascular basement membrane during capillary regression in mouse tracheas after VEGF signaling was blocked with a VEGF-receptor tyrosine kinase inhibitor AG-013736 or soluble receptor construct (VEGF Trap or soluble adenoviral VEGFR-1). Within 1 day, patency was lost and fibrin accumulated in some tracheal capillaries. Apoptotic endothelial cells marked by activated caspase-3 were present in capillaries without blood flow. VEGF inhibition was accompanied by a 19% decrease in tracheal capillaries over 7 days and 30% over 21 days. During this period, desmin/NG2-immunoreactive pericytes moved away from regressing capillaries onto surviving vessels. Empty sleeves of basement membrane, left behind by regressing endothelial cells, persisted for about 2 wk and served as a scaffold for vascular regrowth after treatment ended. The amount of regrowth was limited by the number of surviving basement membrane sleeves. These findings demonstrate that, after inhibition of VEGF signaling, some normal capillaries regress in a systematic sequence of events initiated by a cessation of blood flow and followed by apoptosis of endothelial cells, migration of pericytes away from regressing vessels, and formation of empty basement membrane sleeves that can facilitate capillary regrowth.

Animals↗

Angiopoietin-1 decreases plasma leakage by reducing number and size of endothelial gaps in venules.

Angiopoietin-1 (Ang-1) is essential for remodeling of the primitive vascular plexus and recruitment of mural cells during embryonic development. In the adult vasculature, Ang-1 can reduce plasma leakage in inflammation, but the mechanism of this action is not well understood. In the present study, we determined the magnitude and cellular mechanism of the antileak effect of Ang-1 in the airways of mice. Intravenous injection of bradykinin resulted in leakage of fluorescent microspheres (diameter 25-1,000 nm) from tracheal venules. The leakage peaked in 3-4 min and resolved by 10 min. High-resolution confocal microscopy revealed the presence of focal gaps at intercellular junctions of leaky venules. Genetically engineered Ang-1*, delivered systemically by adenoviral transduction of the liver, reduced leakage of 500-nm microspheres after bradykinin by 69%. The reduction in leakage coincided with a decrease in number and size of endothelial gaps. The proportion of venular surface occupied by endothelial gaps decreased 61%. Microsphere leakage correlated strongly with gap number and size (r2 = 0.89). Together the results suggest that Ang-1 reduces leakage from inflamed venules by restricting the number and size of gaps that form at endothelial cell junctions through effects on intracellular signaling, cytoskeleton, and junction-related molecules.

Angiopoietin-1↗

Mosaic tumor vessels: cellular basis and ultrastructure of focal regions lacking endothelial cell markers.

Endothelial cells of blood vessels in tumors may be thin, fragile, and defective in barrier function. We found previously that the endothelium of vessels in human colon carcinoma xenografts in mice is a mosaic structure. Approximately 85% of tumor vessels have uniform CD31 and/or CD105 immunoreactivity, but the remainder have focal regions that lack these common endothelial markers. The present study assessed the ultrastructure of the vessel lining and the integrity of the basement membrane in these regions. Using immunolabeling and confocal microscopy, we identified blood vessels that lacked CD31 and CD105 immunoreactivity and then analyzed the ultrastructure of these vessels by transmission electron microscopy. Eleven percent of vessels in orthotopic tumors and 24% of vessels in ectopic tumors had defects in CD31 and CD105 staining measuring on average 10.8 microm (range, 1-41.2 microm). Ultrastructural studies identified endothelial cells at 92% of CD31- and CD105-negative sites in orthotopic tumors and 70% of the sites in ectopic tumors. Thus, most regions of tumor vessels that lack CD31 and CD105 immunoreactivity represent attenuated endothelial cells with abnormal expression of endothelial cell markers, but some are gaps between endothelial cells. More than 80% of the defects lacked immunoreactivity for multiple basement membrane proteins.

Animals↗

Long-term and sustained COMP-Ang1 induces long-lasting vascular enlargement and enhanced blood flow.

Vascular enlargement is a characteristic feature of angiopoietin-1 (Ang1)-induced changes in adult blood vessels. However, it is unknown whether tissues having Ang1-mediated vascular enlargement have more blood flow or whether the enlargement is reversible. We have recently created a soluble, stable and potent Ang1 variant, COMP-Ang1. In the present study, we investigated the effects of varied dose and duration of COMP-Ang1 on vascular enlargement and blood flow in the tracheal microvasculature of adult mice and explored a possible mechanism of long-lasting vascular enlargement. We found that COMP-Ang1 administered by adenoviral vector induced long-lasting vascular enlargement and increased tracheal blood flow. In contrast, short-term administration of COMP-Ang1 recombinant protein induced transient vascular enlargement that spontaneously reversed within a month. In both cases, the vascular enlargement resulted from endothelial proliferation. The COMP-Ang1-induced vascular remodeling is mediated mainly through Tie2 activation. Sustained overexpression of Tie2 could participate in the maintenance of vascular changes. Together, our findings indicate that sustained treatment with COMP-Ang1 can produce long-lasting vascular enlargement and increased blood flow.

Adenoviridae↗

Angiopoietin 1 causes vessel enlargement, without angiogenic sprouting, during a critical developmental period.

Early in development, endothelial cells proliferate, coalesce, and sprout to form a primitive plexus of undifferentiated microvessels. Subsequently, this plexus remodels into a hierarchical network of different-sized vessels. Although the processes of proliferation and sprouting are well studied and are dependent on the angiogenic growth factor VEGF, the factors involved in subsequent vessel remodeling are poorly understood. Here, we show that angiopoietin 1 can induce circumferential vessel enlargement, specifically on the venous side of the circulation. This action is due to the ability of angiopoietin 1 to promote endothelial cell proliferation in the absence of angiogenic sprouting; vessel growth without sprouting has not been ascribed to other vascular growth factors, nor has specificity for a particular segment of the vasculature. Moreover, angiopoietin 1 potently mediates widespread vessel enlargement only during a brief postnatal period, in particular, prior to the fourth postnatal week, corresponding to stages in which VEGF inhibition causes widespread vessel regression. These findings show that angiopoietin 1 has a potentially unique role among the vascular growth factors by acting to enlarge blood vessels without inducing sprouting, and also define a critical window of vascular plasticity in neonatal development. Finding the key molecular factors that regulate this plasticity may prove crucial to the further development of pro- and anti-angiogenic therapies.

Age Factors↗

Rapid access of antibodies to alpha5beta1 integrin overexpressed on the luminal surface of tumor blood vessels.

Integrin alpha(5)beta(1) is overexpressed on endothelial cells of tumor vessels and is uniformly and rapidly accessible to antibodies in the bloodstream. Here, we determined whether antibodies rapidly gain access to integrin overexpressed on the abluminal (basolateral) surface of endothelial cells through vascular leakiness or whether the rapid accessibility results instead because the integrin is overexpressed on the luminal (apical) surface of endothelial cells due to loss of cell polarity. Using tumors in RIP-Tag2 transgenic mice as a model, we first compared the binding pattern of intravascular anti-alpha(5)beta(1) integrin antibody with the leakage pattern of nonspecific IgG. The distributions did not match: anti-alpha(5)beta(1) integrin antibody uniformly labeled the tumor vasculature, but IgG was located in patchy sites of leakage. We next injected an antibody to fibrinogen/fibrin, which resulted in patchy labeling of tumors that matched the leakage of IgG and the overall distribution of fibrin in tumors. Similarly, injected antibodies to the basement membrane protein fibronectin, a ligand of alpha(5)beta(1) integrin, or type IV collagen produced patchy sites of leakage instead of uniform labeling of vascular basement membrane. Differences in the kinetics of labeling, which for alpha(5)beta(1) integrin antibody was near maximal by 10 minutes but for the other antibodies gradually increased over 6 hours, indicated differences in accessibility of their respective targets. Isosurface rendering of confocal microscopic images was consistent with antibody binding to alpha(5)beta(1) integrin on the luminal surface of endothelial cells. Together, these findings indicate that the rapid accessibility of alpha(5)beta(1) integrin in RIP-Tag2 tumors results from overexpression of the integrin on the luminal surface of tumor vessels.

Adenoma, Islet Cell↗

Cellular abnormalities of blood vessels as targets in cancer.

Tumor blood vessels have multiple structural and functional abnormalities. They are unusually dynamic, and naturally undergo sprouting, proliferation, remodeling or regression. The vessels are irregularly shaped, tortuous, and lack the normal hierarchical arrangement of arterioles, capillaries and venules. Endothelial cells in tumors have abnormalities in gene expression, require growth factors for survival and have defective barrier function to plasma proteins. Pericytes on tumor vessels are also abnormal. Aberrant endothelial cells and pericytes generate defective basement membrane. Angiogenesis inhibitors can stop the growth of tumor vessels, prune existing vessels and normalize surviving vessels. Loss of endothelial cells is not necessarily accompanied by simultaneous loss of pericytes and surrounding basement membrane, which together can then provide a scaffold for regrowth of tumor vessels. Rapid vascular regrowth reflects the ongoing drive for angiogenesis and bizarre microenvironment in tumors that promote vascular abnormalities and thereby create therapeutic targets.

Angiogenesis Inhibitors↗