Rab35 Governs Apicobasal Polarity Through Regulation of Actin Dynamics During Sprouting Angiogenesis

In early blood vessel development, trafficking programs, such as those using Rab GTPases, are tasked with delivering vesicular cargo with high spatiotemporal accuracy. However, the function of many Rab trafficking proteins remain ill-defined in endothelial tissue; therefore, their relevance to blood vessel development is unknown. Rab35 has been shown to play an enigmatic role in cellular behaviors which differs greatly between tissue-type and organism. Importantly, Rab35 has never been characterized for its potential contribution in sprouting angiogenesis; thus, our goal was to map Rab35s primary function in angiogenesis. Our results demonstrate that Rab35 is critical for sprout formation; in its absence apicobasal polarity is entirely lost in vitro and in vivo. To determine mechanism, we systematically explored established Rab35 effectors and show that none are operative in endothelial cells. However, we find that Rab35 partners with DENNd1c, an evolutionarily divergent guanine exchange factor, to localize to actin. Here, Rab35 regulates actin polymerization, which is required to setup proper apicobasal polarity during sprout formation. Our findings establish that Rab35 is a potent regulator of actin architecture during blood vessel development.

Mitochondrial Dynamics: Pathogenesis and Therapeutic Targets of Vascular Diseases

Vascular diseases, particularly atherosclerosis, are associated with high morbidity and mortality. Endothelial cell (EC) or vascular smooth muscle cell (VSMC) dysfunction leads to blood vessel abnormalities, which cause a series of vascular diseases. The mitochondria are the core sites of cell energy metabolism and function in blood vessel development and vascular disease pathogenesis. Mitochondrial dynamics, including fusion and fission, affect a variety of physiological or pathological processes. Multiple studies have confirmed the influence of mitochondrial dynamics on vascular diseases. This review discusses the regulatory mechanisms of mitochondrial dynamics, the key proteins that mediate mitochondrial fusion and fission, and their potential effects on ECs and VSMCs. We demonstrated the possibility of mitochondrial dynamics as a potential target for the treatment of vascular diseases.

Latanoprost eye drops induce conjunctival lymphatic vessel development

AIM: To investigate the effect of latanoprost eye drops on the conjunctival lymphatics. METHODS: Twenty-four healthy New Zealand White rabbits weighing 1.5 to 2.0 kg were randomly divided into three groups: latanoprost group (n=8) administered with latanoprost eye drops once a day for 2mo, carteolol group (n=8) administered with carteolol eye drops once a day for 2mo, and control group (n=8) without any treatment. The conjunctival tissues in the three groups were extracted to investigate the expression levels of 5’-nucleotidase (5’-Nase) by Western blot, reverse transcription-polymerase chain reaction (RT-PCR), and immunofluorescence staining, respectively. RESULTS: The protein expression level of 5’-Nase was significantly higher in latanoprost group than carteolol group (F=231.175, P<0.001) and control group (P<0.001), while there was no significant difference between the carteolol group and the control group (P>0.05). The mRNA expression level of 5’-Nase in the latanoprost group was also significantly higher than carteolol group (F=71.169 P<0.005) and control group (P<0.005). The conjunctival lymphatics were positive immunofluorescence stained with the 5’-Nase antibodies in the latanoprost group and not stained in the control group. CONCLUSION: Latanoprost eye drops can induce conjunctival lymphangiogenesis which may be concerned in clinical implications.

A ligand-insensitive UNC5B splicing isoform regulates angiogenesis by promoting apoptosis

The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis.

Capillary-associated microglia regulate vascular structure and function through PANX1-P2RY12 coupling

Microglia are brain-resident immune cells with a repertoire of functions in the developing, mature and pathological brain. Their wide-ranging roles in physiology include the clearance of cellular debris, elimination of excess synapses, regulation of neuronal activity and contributions to blood vessel development. Despite these known roles for microglia, the extent of their interactions with the vasculature and potential regulation of vascular physiology has been insufficiently explored. Here, using in vivo acute and longitudinal two-photon imaging in transgenic mice combined with electron microscopy, fixed tissue immunohistochemistry, pharmacological treatments and laser speckle imaging, we document the steady-state interactions between ramified CX3CR1+ myeloid cell somata and capillaries in the brain. We first confirm that these myeloid cells are bona fide microglia by molecular, morphological and ultrastructural approaches. Then we give a detailed spatio-temporal characterization of these capillary-associated microglia (CAMs) comparing and contrasting them with parenchymal microglia (PCMs) in their static, dynamic and chronic morphological activities including during microglial depletion and repopulation. Molecularly, we identify microglial-specific purinergic P2RY12 receptors as a receptor regulating CAM interactions under the control of released purines from pannexin 1 (PANX1) channels. Furthermore, to elucidate roles for microglia in vascular structure and function, we eliminated microglia and showed that this triggered capillary dilation, blood flow increase, and impaired vasodilative responses. We find that P2RY12-/- and PANX1-/- mice recapitulate these vascular impairments suggesting purines released through PANX1 channels play important roles in activating microglial P2RY12 receptors to regulate neurovascular structure and function.

A Comprehensive Rehabilitation of a known Case of Leprosy Operated for Midshaft Femur Fracture

Background: A persistent infection triggered by Mycobacterium leprae is also known as leprosy or Hansen's disease, transmitting by tiny droplets of the nose and mouth to the skin and peripheral nerves, producing disability. Leprosy therapy is based on the combination of the rifampicin, dispone and clofazimine (MDT) three-drug regimen. In patients who undergo hormone therapy, avascular femoral necrosis (ANFH) or femoral head osteonecrosis (ONFH) may occur, causing steroid-induced femoral head avascular necrosis (SANFH) Core decompression (CD) reduces bone pressure, opens the hardening area, prevents osteonecrosis repair, promotes blood vessel development through the tunnel for decompression, increases bone replacement and delays osteonecrosis. Patient information, diagnosis and therapeutic interventions: In this case, we found a 20 years old girl known case of leprosy, was on corticosteroids for two and half years. After an increase in dosage of corticosteroids she began difficult for her walk and do her activities of daily living. She visited Acharya Vinoba Bhave Rural Hospital (AVBRH), DMIMS (DU) Sawangi Meghe, Wardha, Maharashtra, India where she got to know about necrosis of head of femur of both lower limbs. She underwent core decompression surgery of bilateral femoral head. For further management she was referred to Physiotherapy Department. Outcomes and Conclusion: this case, we found that a patient who is young who had Midshaft femur fracture with interlock nailing and sever kinesiophobia, affecting rehabilitation, was able to resume her ADLs independently.