Bone Marrow-derived Endothelial Cells Research Articles

Engineering Biomimetic Microvascular Capillary Networks in Hydrogel Fibrous Scaffolds via Microfluidics-Assisted Co-Axial Wet-Spinning.

The microvascular bed plays a crucial role in establishing nutrient exchange and waste removal, as well as maintaining tissue metabolic activity in the human body. However, achieving microvascularization of engineered 3D tissue constructs is still an unsolved challenge. In this work, we developed biomimetic cell-laden hydrogel microfibers recapitulating oriented microvascular capillary-like networks by using a 3D bioprinting technique combined with microfluidics-assisted coaxial wet-spinning. Highly packed and aligned bundles embedding a coculture of human bone marrow-derived mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) were produced by simultaneously extruding two different bioinks. To this aim, core-shell fibers were wet-spun in a coagulation bath to collect the scaffolds later on a rotary drum. Initially, the versatility of the proposed system was assessed for the extrusion of multimaterial core-shell hydrogel fibers. Subsequently, the platform was validated for the in vitro biofabrication of samples promoting optimal cell alignment along the fiber axis. After 3 weeks of culture, such fiber configuration resulted in the development of an oriented capillary-like network within the fibrin-based core and in the endothelial-specific CD31 marker expression upon MSC/HUVEC maturation. Synergistically, the vertical arrangement of the coaxial nozzle coupled with the rotation of the fiber collector facilitated the rapid creation of tightly packed bundles characterized by a dense, oriented, and extensively branched capillary network. Notably, such findings suggest that the proposed biofabrication strategy can be used for the microvascularization of tissue-specific 3D constructs.

A Single-Cell RNA Sequencing Guided Multienzymatic Hydrogel Design for Self-Regenerative Repair in Diabetic Mandibular Defects.

Conventional bone tissue engineering materials struggle to reinstate physiological bone remodeling in a diabetic context, primarily due to the compromised repolarization of proinflammatory macrophages to anti-inflammatory macrophages. Here, leveraging single-cell RNA sequencing (scRNA-seq) technology, the pivotal role of nitric oxide (NO) and reactive oxygen species (ROS) is unveiled in impeding macrophage repolarization during physiological bone remodeling amidst diabetes. Guided by scRNA-seq analysis, we engineer a multienzymatic bone tissue engineering hydrogel scaffold (MEBTHS) composed is engineered of methylpropenylated gelatin hydrogel integrated with ruthenium nanozymes, possessing both Ru0 and Ru4+ components. This design facilitates efficient NO elimination via Ru0 while simultaneously exhibiting ROS scavenging properties through Ru4+. Consequently, MEBTHS orchestrates macrophage reprogramming by neutralizing ROS and reversing NO-mediated mitochondrial metabolism, thereby rejuvenating bone marrow-derived mesenchymal stem cells and endothelial cells within diabetic mandibular defects, producing newly formed bone with quality comparable to that of normal bone. The scRNA-seq guided multienzymatic hydrogel design fosters the restoration of self-regenerative repair, marking a significant advancement in bone tissue engineering.

Bone marrow cells contribute to seven different endothelial cell populations in the heart

Understanding the mechanisms underlying vascular regeneration in the heart is crucial for developing novel therapeutic strategies for myocardial ischemia. This study investigates the contribution of bone marrow-derived cells to endothelial cell populations in the heart, and their role in cardiac function and coronary circulation following repetitive ischemia (RI). Chimeric rats were created by transplanting BM cells from GFP female rats into irradiated male recipients. After engraftment chimeras were subjected to RI for 17 days. Vascular growth was assessed from recovery of cardiac function and increases in myocardial blood flow during LAD occlusion. After sorting GFP+ BM cells from heart and bone of Control and RI rats, single-cell RNA sequencing was implemented to determine the fate of BM cells. Our in vivo RI model demonstrated an improvement in cardiac function and myocardial blood flow after 17 days of RI with increased capillary density in the rats subjected to RI compared to Controls. Single-cell RNA sequencing of bone marrow cells isolated from rats' hearts identified distinct endothelial cell (EC) subpopulations. These ECs exhibited heterogeneous gene expression profiles and were enriched for markers of capillary, artery, lymphatic, venous, and immune ECs. Furthermore, BM-derived ECs in the RI group showed an angiogenic profile, characterized by upregulated genes associated with blood vessel development and angiogenesis. This study elucidates the heterogeneity of bone marrow-derived endothelial cells in the heart and their response to repetitive ischemia, laying the groundwork for targeting specific subpopulations for therapeutic angiogenesis in myocardial ischemia.

Bifunctional mesoporous glasses for bone tissue engineering: Biological effects of doping with cerium and polyphenols in 2D and 3D in vitro models

Bifunctional mesoporous glasses for bone tissue engineering: Biological effects of doping with cerium and polyphenols in 2D and 3D in vitro models

Plasma-derived extracellular matrix for xenofree and cost-effective organoid modeling for hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) causes significant cancer mortality worldwide. Cancer organoids can serve as useful disease models by high costs, complexity, and contamination risks from animal-derived products and extracellular matrix (ECM) that limit its applications. On the other hand, synthetic ECM alternatives also have limitations in mimicking native biocomplexity. This study explores the development of a physiologically relevant HCC organoid model using plasma-derived extracellular matrix as a scaffold and nutritive biomatrix with different cellularity components to better mimic the heterogenous HCC microenvironment. Plasma-rich platelet is recognized for its elevated levels of growth factors, which can promote cell proliferation. By employing it as a biomatrix for organoid culture there is a potential to enhance the quality and functionality of organoid models for diverse applications in biomedical research and regenerative medicine and to better replicate the heterogeneous microenvironment of HCC.MethodTo generate the liver cancer organoids, HUH-7 hepatoma cells were cultured alone (homogenous model) or with human bone marrow-derived mesenchymal stromal cells and human umbilical vein endothelial cells (heterogeneous model) in plasma-rich platelet extracellular matrix (ECM). The organoids were grown for 14 days and analyzed for cancer properties including cell viability, invasion, stemness, and drug resistance.ResultsHCC organoids were developed comprising HUH-7 hepatoma cells with or without human mesenchymal stromal and endothelial cells in plasma ECM scaffolds. Both homogeneous (HUH-7 only) and heterogeneous (mixed cellularity) organoids displayed viability, cancer hallmarks, and chemoresistance. The heterogeneous organoids showed enhanced invasion potential, cancer stem cell populations, and late-stage HCC genetic signatures versus homogeneous counterparts.ConclusionThe engineered HCC organoids system offers a clinically relevant and cost-effective model to study liver cancer pathogenesis, stromal interactions, and drug resistance. The plasma ECM-based culture technique could enable standardized and reproducible HCC modeling. It could also provide a promising option for organoid culture and scaling up.

Abstract 5551: Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment

Abstract Several mutations have been identified that are associated with an increased risk of triple-negative breast cancer (TNBC), including those that are deleterious in the BRCA gene. TNBC is associated with the worst prognosis and the highest incidence of brain metastasis (30%) among all subtypes of BC. Despite objective responses to poly (ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA-mutated TNBC, benefits are transitory. Furthermore, our understanding of the effect of PARP inhibitors (PARPi) in treating breast cancer brain metastasis (BCBM) and modulating its tumor microenvironment (TME) is still lacking. To this end, we analyzed the brain TME of BRCA-mutated BCBM in the absence or presence of treatment with PARPi. Interestingly, we found that the immune TME of the brain hinder the antitumor activity of PARPi by upregulating multiple immunosuppressive molecules, including PD-L1. Furthermore, we found that BCBM overexpress P-selectin through its interaction with the tumor-associated microglia, bone marrow-derived macrophages and endothelial cells in the TME. Thus, we designed a novel nanoparticle (NP) targeting P-selectin to serve as a brain-penetrant delivery system for the treatment of BCBM. In order to target BRCA-mutated BCBM, we harnessed our novel P-selectin-targeted NPs to entrap PARPi and other immune modulators that we found to exert synergistic activity when combined. To evaluate the antitumor activity of our P-selectin-targeted NPs, we established 3-dimensional (3D) ex vivo and in vivo BRCA-mutated BCBM models. Importantly, we saw favorable effects of the P-selectin-targeted NPs in comparison to the combination of the free drugs, suggesting that out targeted-NPs overcome the TME-mediated resistance to PARPi through the modulation of the immunosuppressive microenvironment of the brain. Citation Format: Rami Khoury, Ron Kleiner, Eilam Yeini, Daniel Rodriguez Ajamil, Sahar Israeli Dangoor, Tamer Sanalla, Iris Barshack, Roni Satchi-Fainaro. Targeted nanoparticles co-delivering PARP inhibitor and other immune modulators overcome the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5551.

Nanoclay Hydrogel Microspheres with a Sandwich-Like Structure for Complex Tissue Infection Treatment.

Addressing complex tissue infections remains a challenging task because of the lack of effective means, and the limitations of traditional bioantimicrobial materials in single-application scenarios hinder their utility for complex infection sites. Hence, the development of a bioantimicrobial material with broad applicability and potent bactericidal activity is necessary to treat such infections. In this study, a layered lithium magnesium silicate nanoclay (LMS) is used to construct a nanobactericidal platform. This platform exhibits a sandwich-like structure, which is achieved through copper ion modification using a dopamine-mediated metallophenolic network. Moreover, the nanoclay is encapsulated within gelatin methacryloyl (GelMA) hydrogel microspheres for the treatment of complex tissue infections. The results demonstrate that the sandwich-like micro- and nanobactericidal hydrogel microspheres effectively eradicated Staphylococcus aureus (S. aureus) while exhibiting excellent biocompatibility with bone marrow-derived mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs). Furthermore, the hydrogel microspheres upregulated the expression levels of osteogenic differentiation and angiogenesis-related genes in these cells. In vivo experiments validated the efficacy of sandwich-like micro- and nanobactericidal hydrogel microspheres when injected into deep infected tissues, effectively eliminating bacteria and promoting robust vascular regeneration and tissue repair. Therefore, these innovative sandwich-like micro- and nanobacteriostatic hydrogel microspheres show great potential for treating complex tissue infections.

Antisenescence ZIF-8/Resveratrol Nanoformulation with Potential for Enhancement of Bone Fracture Healing in the Elderly.

Accumulation of senescent cells in the elderly impairs bone homeostasis. It is important to alleviate cell senescence and scavenge excessive oxidative stress for enhanced bone fracture healing in elderly patients. In this study, resveratrol (RSV), an antioxidant drug, was encapsulated in a biocompatible zeolitic imidazolate framework-8 (ZIF-8) nanoparticle to protect it from oxidation and improve its bioavailability. Cells responsible for bone healing, including osteoblasts, bone marrow-derived mesenchymal stem cells (BMSCs), macrophages, and endothelial cells, were used to evaluate the regulatory role of the nanoformulation in the alleviation of cellular senescence and promotion of cell functions. It was proved that the nanoformulation sustainably released RSV with well-preserved bioactivity and improved bioavailability. Cell experiments confirmed that ZIF-8/RSV was capable of alleviating the senescence of cells [human osteoblasts (HOBs), BMSCs, H2O2-induced senescent vascular endothelial cells (HUVECs)] and scavenging excessive intracellular reactive oxygen species (ROS). Excitingly, the ZIF-8/RSV improved the osteogenic ability of senescent osteoblasts and promoted macrophage M2 polarization. In addition, the ZIF-8/RSV also enhanced the angiogenic function of senescent HUVECs. More importantly, the ZIF-8/RSV nanoformulation outperformed the REV alone, indicating the critical role of encapsulation using ZIF-8. These findings suggest that the ZIF-8/RSV nanoformulation exhibits potential for bone fracture treatment in elderly patients.

Injectable engineered micro/nano-complexes trigger the reprogramming of bone immune epigenetics

Injectable engineered micro/nano-complexes trigger the reprogramming of bone immune epigenetics

Characterization and assessment of lung and bone marrow derived endothelial cells and their bone regenerative potential.

Angiogenesis is important for successful fracture repair. Aging negatively affects the number and activity of endothelial cells (ECs) and subsequently leads to impaired bone healing. We previously showed that implantation of lung-derived endothelial cells (LECs) improved fracture healing in rats. In this study, we characterized and compared neonatal lung and bone marrow-derived endothelial cells (neonatal LECs and neonatal BMECs) and further asses3sed if implantation of neonatal BMECs could enhance bone healing in both young and aged mice. We assessed neonatal EC tube formation, proliferation, and wound migration ability in vitro in ECs isolated from the bone marrow and lungs of neonatal mice. The in vitro studies demonstrated that both neonatal LECs and neonatal BMECs exhibited EC traits. To test the function of neonatal ECs in vivo, we created a femoral fracture in young and aged mice and implanted a collagen sponge to deliver neonatal BMECs at the fracture site. In the mouse fracture model, endochondral ossification was delayed in aged control mice compared to young controls. Neonatal BMECs significantly improved endochondral bone formation only in aged mice. These data suggest BMECs have potential to enhance aged bone healing. Compared to LECs, BMECs are more feasible for translational cell therapy and clinical applications in bone repair. Future studies are needed to examine the fate and function of BMECs implanted into the fracture sites.

Therapeutic Targeting Notch2 Protects Bone Micro-Vasculatures from Methotrexate Chemotherapy-Induced Adverse Effects in Rats.

Intensive cancer chemotherapy is well known to cause bone vasculature disfunction and damage, but the mechanism is poorly understood and there is a lack of treatment. Using a rat model of methotrexate (MTX) chemotherapy (five once-daily dosses at 0.75 mg/kg), this study investigated the roles of the Notch2 signalling pathway in MTX chemotherapy-induced bone micro-vasculature impairment. Gene expression, histological and micro-computed tomography (micro-CT) analyses revealed that MTX-induced micro-vasculature dilation and regression is associated with the induction of Notch2 activity in endothelial cells and increased production of inflammatory cytokine tumour necrosis factor alpha (TNFα) from osteoblasts (bone forming cells) and bone marrow cells. Blockade of Notch2 by a neutralising antibody ameliorated MTX adverse effects on bone micro-vasculature, both directly by supressing Notch2 signalling in endothelial cells and indirectly via reducing TNFα production. Furthermore, in vitro studies using rat bone marrow-derived endothelial cell revealed that MTX treatment induces Notch2/Hey1 pathway and negatively affects their ability in migration and tube formation, and Notch2 blockade can partially protect endothelial cell functions from MTX damage.

Abstract TMP5: Bone Marrow-derived And Clonally Expanded Alk1 - Endothelial Cells Contribute To Brain Arteriovenous Malformation In Mice

Background and Purpose: Homozygous mutation in arteriovenous malformation (AVM) causative genes in a fraction of endothelial cells (ECs) causes brain AVMs (bAVMs). Heterozygous mutation of endoglin, an AVM causative gene, in bone marrow (BM) caused capillary dysplasia in mouse brain. We tested if (1) homozygous mutation of activin receptor-like kinase 1 ( Alk1, another AVM causative gene) in BM derived ECs (BMDECs) can cause bAVM in brain angiogenic region, (2) Alk1 - ECs clonally expand in bAVM, and (3) the burden of Alk1 - ECs correlates with bAVM severity. Methods: The BMs of Pdgfb iCreER; Alk1 2 f/2f ;Ai14 mice with EC-specific tamoxifen-inducible Cre and Alk1 floxed alleles were transplanted into wild-type mice to analyze the role of BMDECs in bAVM development. Pdgfb iCreER; Alk1 2 f/2f ;confetti +/- mice with Cre-regulated confetti transgene were used to study EC clonal expansion. Brain AVMs were induced by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor followed by intra-peritoneal injection of tamoxifen. Results: Wild-type mice transplanted with Pdgfb iCreER; Alk1 2 f/2f ;Ai14 BM developed bAVMs after bAVM induction. Recombined BMDECs were detected in bAVMs. The presence of clusters of ECs expressing same confetti color in bAVMs suggests that Alk1 - ECs had been clonally expanded. Increasing tamoxifen dose increased the number of Alk1 - ECs and abnormal vessels in bAVMs of Pdgfb iCreER; Alk1 2 f/2f mice. Conclusion: Homozygous mutation of Alk1 in BMDECs is sufficient to cause bAVM development in brain angiogenic region; clonal expansion of Alk1 - ECs provides a likely mechanism for how a fraction of mutant ECs causes bAVM; and the burden of Alk1 - ECs correlates with AVM severity.

Bone Marrow-Derived Alk1 Mutant Endothelial Cells and Clonally Expanded Somatic Alk1 Mutant Endothelial Cells Contribute to the Development of Brain Arteriovenous Malformations in Mice.

We have previously demonstrated that deletion of activin receptor-like kinase 1 (Alk1) or endoglin in a fraction of endothelial cells (ECs) induces brain arteriovenous malformations (bAVMs) in adult mice upon angiogenic stimulation. Here, we addressed three related questions: (1) could Alk1- mutant bone marrow (BM)-derived ECs (BMDECs) cause bAVMs? (2) is Alk1- ECs clonally expended during bAVM development? and (3) is the number of mutant ECs correlates to bAVM severity? For the first question, we transplanted BM from PdgfbiCreER;Alk12f/2f mice (EC-specific tamoxifen-inducible Cre with Alk1-floxed alleles) into wild-type mice, and then induced bAVMs by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor and intra-peritoneal injection of tamoxifen. For the second question, clonal expansion was analyzed using PdgfbiCreER;Alk12f/2f;confetti+/- mice. For the third question, we titrated tamoxifen to limit Alk1 deletion and compared the severity of bAVM in mice treated with low and high tamoxifen doses. We found that wild-type mice with PdgfbiCreER;Alk12f/2f BM developed bAVMs upon VEGF stimulation and Alk1 gene deletion in BMDECs. We also observed clusters of ECs expressing the same confetti color within bAVMs and significant proliferation of Alk1- ECs at early stage of bAVM development, suggesting that Alk1- ECs clonally expanded by local proliferation. Tamoxifen dose titration revealed a direct correlation between the number of Alk1- ECs and the burden of dysplastic vessels in bAVMs. These results provide novel insights for the understanding of the mechanism by which a small fraction of Alk1 or endoglin mutant ECs contribute to development of bAVMs.

A polydopamine-assisted strontium-substituted apatite coating for titanium promotes osteogenesis and angiogenesis via FAK/MAPK and PI3K/AKT signaling pathways

A polydopamine-assisted strontium-substituted apatite coating for titanium promotes osteogenesis and angiogenesis via FAK/MAPK and PI3K/AKT signaling pathways

Bioinspired Redwood-Like Scaffolds Coordinated by In Situ-Generated Silica-Containing Hybrid Nanocoatings Promote Angiogenesis and Osteogenesis both In Vitro and In Vivo.

Inspired by natural redwood and bone, a biomimetic strategy is presented to develop a highly bioactive redwood-like nanocomposite via radial freeze casting of biocompatible hydrogels followed by the in situ coprecipitation of a Si-containing CaP hybrid nanocoating (SCPN). The engineered material displays radially aligned macrochannels and a porous network structure similar to those of natural redwood. In addition to acting as a mechanical reinforcement, introducing SCPNs into the weak redwood-like scaffold yields not only a nanoroughened surface topography, a low swelling ratio, retarded enzymatic degradation, and enhanced protein absorption abilities but also the sustained sequential release of Si and Ca ions, thereby providing essential biophysical and biochemical cues for effective bone regeneration. Benefiting from the redwood-like structures and bioactive SCPNs, the biomimetic materials create a favorable microenvironment for promoting the initial adhesion, spreading, proliferation, and migration of bone marrow-derived mesenchymal stem cells and human umbilical vein endothelial cells. Furthermore, the in vitro and in vivo data showed that the biocompatible redwood-like scaffold with precipitated SCPN can synergistically promote osteogenesis and angiogenesis in their aligned direction. Collectively, this work presents a novel bioinspired redwood-like material with multifunctional properties that provides new insight into bone defect repair.

Restoration of critical defects in the rabbit mandible using osteoblasts and vascular endothelial cells co-cultured with vascular stent-loaded nano-composite scaffolds

Restoration of critical defects in the rabbit mandible using osteoblasts and vascular endothelial cells co-cultured with vascular stent-loaded nano-composite scaffolds

Directly construct microvascularization of tissue engineering trachea in orthotopic transplantation

Directly construct microvascularization of tissue engineering trachea in orthotopic transplantation

Hypoxia alleviates dexamethasone-induced inhibition of angiogenesis in cocultures of HUVECs and rBMSCs via HIF-1\u03b1

Background and aimInadequate vascularization is a challenge in bone tissue engineering because internal cells are prone to necrosis due to a lack of nutrient supply. Rat bone marrow-derived mesenchymal stem cells (rBMSCs) and human umbilical vein endothelial cells (HUVECs) were cocultured to construct prevascularized bone tissue in osteogenic induction medium (OIM) in vitro. The angiogenic capacity of HUVECs was limited in the coculture system. In this study, the effects of the components in the medium on HUVEC angiogenesis were analyzed.MethodsThe coculture system was established in OIM. Alizarin red staining and alkaline phosphatase staining were used to assess the osteogenic ability of MSCs. A Matrigel tube assay was used to assess the angiogenic ability of HUVECs in vitro. The proliferation of HUVECs was evaluated by cell counting and CCK-8 assays, and migration was evaluated by the streaked plate assay. The expression levels of angiogenesis-associated genes and proteins in HUVECs were measured by qRT-PCR and Western blotting, respectively.ResultsDexamethasone in the OIM suppressed the proliferation and migration of HUVECs, inhibiting the formation of capillary-like structures. Our research showed that dexamethasone stimulated HUVECs to secrete tissue inhibitor of metalloproteinase (TIMP-3), which competed with vascular endothelial growth factor (VEGF-A) to bind to vascular endothelial growth factor receptor 2 (VEGFR2, KDR). This effect was related to inhibiting the phosphorylation of ERK and AKT, which are two downstream targets of KDR. However, under hypoxia, the enhanced expression of hypoxia-inducible factor-1α (HIF-1α) decreased the expression of TIMP-3 and promoted the phosphorylation of KDR, improving HUVEC angiogenesis in the coculture system.ConclusionCoculture of hypoxia-preconditioned HUVECs and MSCs showed robust angiogenesis and osteogenesis in OIM, which has important implications for prevascularization in bone tissue engineering in the future.

An Alginate-Based Hydrogel with a High Angiogenic Capacity and a High Osteogenic Potential.

In bone tissue engineering, autologous cells are combined with osteoconductive scaffolds and implanted into bone defects. The major challenge is the lack of post-implantation vascular growth into biomaterial. The objective of the present study was to develop a new alginate-based hydrogel that enhances the regeneration of bone defects after surgery. The viability of human bone marrow-derived mesenchymal stem cells (BM-MSCs) or human endothelial cells (ECs) cultured alone or together on the hydrogel was analyzed for 24 and 96 h. After seeding, the cells self-assembled and aggregated to form clusters. For functional validation, empty or cellularized hydrogel matrices were implanted ectopically at subcutaneous sites in nude mice. After 2 months, the matrices were explanted. Transplanted human cells were present, and we observed vessels expressing human von Willebrand factor (resulting from the incorporation of transplanted ECs into neovessels and/or the differentiation of BM-MSCs into ECs). The addition of BM-MSCs improved host vascularization and neovessel formation from human cells, relative to ECs alone. Although we did not observe bone formation, the transplanted BM-MSCs were able to differentiate into osteoblasts. This new biomaterial provided an appropriate three-dimensional environment for transplanted cells and has a high angiogenic capacity and an osteogenic potential.

The Anti-Angiogenic Effects of Anti-Human Immunodeficiency Virus Drugs.

The growth and metastasis of malignant tumors benefit from the formation of blood vessels within the tumor area. There, new vessels originate from angiogenesis (the sprouting of pre-existing neighboring vessels) and/or vasculogenesis (the mobilization of bone marrow-derived endothelial cell precursors which incorporate in tumor vasculature and then differentiate into mature endothelial cells). These events are induced by soluble molecules (the angiogenic factors) and modulated by endothelial cell interactions with the perivascular matrix. Given angiogenesis/vasculogenesis relevance to tumor progression, anti-angiogenic drugs are often employed to buttress surgery, chemotherapy or radiation therapy in the treatment of a wide variety of cancers. Most of the anti-angiogenic drugs have been developed to functionally impair the angiogenic vascular endothelial growth factor: however, this leaves other angiogenic factors unaffected, hence leading to drug resistance and escape. Other anti-angiogenic strategies have exploited classical inhibitors of enzymes remodeling the perivascular matrix. Disappointingly, these inhibitors have been found toxic and/or ineffective in clinical trials, even though they block angiogenesis in pre-clinical models. These findings are stimulating the identification of other anti-angiogenic compounds. In this regard, it is noteworthy that drugs utilized for a long time to counteract human immune deficiency virus (HIV) can directly and effectively hamper molecular pathways leading to blood vessel formation. In this review the mechanisms leading to angiogenesis and vasculogenesis, and their susceptibility to anti-HIV drugs will be discussed.