C1qr and C1qrl redundantly regulate angiogenesis in zebrafish through controlling endothelial Cdh5.

Angiogenesis plays central role in the formation of functional circulation system. Characterizations of the involved factors and signaling pathways remain to be the key interest in the angiogenesis research. In this report, we showed that c1qr/cd93 and c1qrl/clec14a are specifically expressed in the vascular endothelial cells during zebrafish development. Single mutation of c1qr or c1qrl is associated with slightly malformation of inter-segmental vessels (ISVs), whereas double mutant exhibits severe defects in the ISVs formation without affecting early vasculogenesis. Further studies reveal that the endothelial-endothelial junctional molecule Cdh5 becomes absent in the ISVs of the double mutant. Replenishment of Cdh5 efficiently rescue the impaired angiogenesis in the c1qr/c1qrl double mutant. These data demonstrate that c1qr and c1qrl redundantly regulate angiogenesis through controlling the expression of the endothelial junctional molecule Cdh5, thus playing an important role in angiogenesis.

First Trimester CD93 as a Novel Marker of Preeclampsia and Its Complications: A Pilot Study.

INTRODUCTION: CD93 plays a crucial role in endothelial homeostasis and angiogenesis. Recently its role in hypertension has been investigated, holding promise for novel targeted diagnostic and therapeutic strategies. AIM: We assessed for the first time differences in first trimester serum CD93 levels in women who lately developed preeclampsia (PE) vs. normotensive pregnancy (NP). METHODS: First trimester serum CD93 concentrations were assessed in a multicenter cohort of 83 women (34 PE and 49 NP) by ELISA Immunoassay. RESULTS: Serum CD93 was lower in women who developed PE vs. NP (111.8 ± 24.4 vs. 137.5 ± 22.3 ng/ml; p < 0.001). Serum CD93 was associated with a decreased risk of developing PE (OR 0.950, 95% CI 0.922-0.978) and composite neonatal outcome (OR 0.952, CI 0.923-0.982), after adjustment for confounders. CONCLUSIONS: PE is accompanied by decreased serum CD93 levels. CD93 might play a role during placentation leading to defective angiogenesis, vascular dysfunction, and PE development.

Diagnostic and Prognostic Role of CD93 in Cardiovascular Disease: A Systematic Review.

INTRODUCTION: Cluster of Differentiation (CD) 93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp) is a transmembrane glycoprotein that can also be present in a soluble (sCD93) form. Recent studies have investigated the role of this protein in cardiovascular disease (CVD). The present systematic review aims to assess the associations between CD93 and cardiovascular (CV) risk factors and disease at both the proteomic and genomic levels. METHODS: We conducted systematic searches in the PubMed, EMBASE, and Web of Science databases to identify all human studies since inception to February 2023 that investigated the role of CD93 in CV risk factors, CVD, and CV-associated outcomes. The data collection and analysis have been independently conducted by two reviewers. The search terms included: cardiovascular, heart failure, acute stroke, myocardial infarction, stroke, peripheral artery disease, cardiovascular death, MACE, hypertension, metabolic syndrome, hyperuricemia, diabetes, cd93, c1qr, C1qR1, complement protein 1 q subcomponent receptor. RESULTS: A total of 182 references were identified, and 15 studies investigating the associations between CD93 protein levels or CD93 genetic polymorphisms and the development or prevalence of CV risk factors (i.e., hypertension, dyslipidemia, and obesity) and CVD (i.e., heart failure, coronary artery disease, and ischemic stroke) were included. Although promising, the quality and dimension of the analyzed studies do not allow for a definitive answer to the question of whether CD93 may hold diagnostic and prognostic value in CVD.

Role of CD93 in Health and Disease.

CD93 (also known as complement protein 1 q subcomponent receptor C1qR1 or C1qRp), is a transmembrane glycoprotein encoded by a gene located on 20p11.21 and composed of 652 amino acids. CD93 can be present in two forms: soluble (sCD93) and membrane-bound (CD93). CD93 is mainly expressed on endothelial cells, where it plays a key role in promoting angiogenesis both in physiology and disease, such as age-related macular degeneration and tumor angiogenesis. In fact, CD93 is highly expressed in tumor-associated vessels and its presence correlates with a poor prognosis, poor immunotherapy response, immune cell infiltration and high tumor, node and metastasis (TNM) stage in many cancer types. CD93 is also expressed in hematopoietic stem cells, cytotrophoblast cells, platelets and many immune cells, i.e., monocytes, neutrophils, B cells and natural killer (NK) cells. Accordingly, CD93 is involved in modulating important inflammatory-associated diseases including systemic sclerosis and neuroinflammation. Finally, CD93 plays a role in cardiovascular disease development and progression. In this article, we reviewed the current literature regarding the role of CD93 in modulating angiogenesis, inflammation and tumor growth in order to understand where this glycoprotein could be a potential therapeutic target and could modify the outcome of the abovementioned pathologies.

cC1qR/CR and gC1qR/p33: observations in cancer.

The survival and growth of a primary tumor depends, by and large, on three major events: immune evasion, angiogenesis and metastasis. Tumor cells are "modified self", and as such express a plethora of modified surface antigens capable of inducing antibody production. Anti-tumor cell antibodies should, in theory, activate complement resulting in cell destruction. But this is not the case. Akin to many pathogenic microorganisms whose survival depends on evading the immune system, cancer cells have also evolved diverse mechanisms to prevent host mediated cell destruction by either retaining critical regulatory molecules or by hijacking host proteins to ensure their survival. Although immune evasion, angiogenesis and metastasis are complex biological processes involving a myriad of tumor associated proteins, enzymes, and cytokines, C1qRs can, nonetheless play an important role in all or part of these processes. Although both cC1qR/CR and gC1qR are expressed by all somatic cells, with the exception of red blood cells, both are highly upregulated on almost all types of tumors. It is not surprising therefore that blockade of C1qR on tumor cells inhibits their proliferation suggesting the significance of C1qRs in tumor growth and progression. Interestingly, the two C1q receptors: cC1qR/CR and gC1qR play a differential role in carcinogenesis. While gC1qR promotes tumor cell survival by enhancing angiogenesis and metastasis and also by contributing to the hypercoagulable and prothrombotic microenvironment, cC1qR/CR expression represents a pro-phagocytic "eat-me" signal through which cC1qR/CR expressing tumor cells are tagged for destruction by macrophages. The data accumulated to date therefore identify gC1qR and cC1qR/CR as potential targets for the design of either protein-based, antibody-based or chemical based therapeutic intervention that could be used to enhance conventional anti-cancer therapy. The inhibition of tumor cell proliferation by monoclonal antibody recognizing the C1q site on gC1qR, as well as the identification of agents such as anthracyclin that enhance cC1qR/CR expression on tumor cells, are indeed steps in the right direction.