key: cord-273595-fkk4ry62 authors: Jing, Yan; Run-Qian, Li; Hao-Ran, Wang; Hao-Ran, Chen; Ya-Bin, Liu; Yang, Gao; Fei, Chen title: Potential influence of COVID-19/ACE2 on the female reproductive system date: 2020-05-04 journal: Mol Hum Reprod DOI: 10.1093/molehr/gaaa030 sha: doc_id: 273595 cord_uid: fkk4ry62 The 2019 novel coronavirus (2019-nCoV) appeared in December 2019 and then spread throughout the world rapidly. The virus invades the target cell by binding to angiotensin-converting enzyme (ACE) 2 and modulates the expression of ACE2 in host cells. ACE2, a pivotal component of the renin-angiotensin system, exerts its physiological functions by modulating the levels of angiotensin II (Ang II) and Ang-(1-7). We reviewed the literature that reported the distribution and function of ACE2 in the female reproductive system, hoping to clarify the potential harm of 2019-nCoV to female fertility. The available evidence suggests that ACE2 is widely expressed in the ovary, uterus, vagina and placenta. Therefore, we believe that apart from droplets and contact transmission, the possibility of mother-to-child and sexual transmission also exists. Ang II, ACE2 and Ang-(1-7) regulate follicle development and ovulation, modulate luteal angiogenesis and degeneration, and also influence the regular changes in endometrial tissue and embryo development. Taking these functions into account, 2019-nCoV may disturb the female reproductive functions through regulating ACE2. Corona virus disease 2019 is an emerging acute communicable disease that was identified in patients with pneumonia in December 2019, which was declared a pandemic by the World Health Organization on 11th March, 2020. A total of 2,719,896 laboratory-confirmed cases and 187,705 deaths have been reported as of 25th April, 2020 (World Health Organization, 2020 . Epidemiologically, the genome of the 2019 novel coronavirus (2019-nCoV) is composed of 29,891 nucleotides, with an 89% identity to bat SARS-like-CoVZXC21 and 82% to human SARS-CoV (Chan et al., 2020) . 2019-nCoV infects the target cell by binding to angiotensin-converting enzyme (ACE) 2 through its surface spike protein Zhou et al., 2020) , modulates the expression of ACE2 and causes severe injuries, similar to SARS-CoV (Kuba et al., 2005; Wang and Cheng, 2020) . ACE2 is a zinc metalloprotease which shares homology with ACE in its catalytic domain (Donoghue et al., 2000) , and is composed of 805 amino acids including a 17-amino acid N-terminal signal sequence and a C-terminal membrane binding domain (Tipnis et al., 2000) . ACE2 contains a single HEXXH zinc-binding motif and is able to hydrolyze angiotensin I (Ang I) to produce angiotensin-(1-9) and also has a high affinity for angiotensin II (Ang II) to generate Ang-(1-7) (Vickers et al., 2002) . Ang II, the major component of the ACE/Ang II/AT1 (angiotensin II type 1) axis, facilitates vasoconstriction, promotes cell proliferation (Bataller et al., 2000; Campbell-Boswell and Robertson, 1981; Hiruma et al., 1997; Ray et al., 1991) , and maintains the hydro-salinity balance (Hall et al., 1977; Johnson and Malvin, 1977) . As an important modulator of the human renin-angiotensin system, Ang-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas and specifically inhibits Ang II by the antagonism of AT1 receptors (Roks et al., 1999) . Moreover, Ang-(1-7) enhances vasodilation (Brosnihan et al., 1998; Oliveira et al., 1999) , protects the heart (Ferreira et al., 2001; Iwata et al., 2005; Santos et al., 2004) and alleviates metabolic syndrome (Giani et al., 2009; Liu et al., 2012) . Evidence has been accumulating that besides lung injury, 2019-nCoV also damages the human heart Zheng et al., 2020) , liver (Chen et al., 2020c; Zhang et al., 2020b) , kidney (Chen et al., 2020c; Huang et al., 2020; and nervous system (Li et al., 2020c; Mao et al., 2020) . Recently, cases of COVID-19 during pregnancy have been reported Liu et al., 2020; Zhu et al., 2020) , but the influence of 2019-nCoV on the female reproductive system needs further investigation. In this review, we analyzed the distribution and function of ACE2, trying to predict the possible targets and transmission routes, as well as the influence on the female reproductive system, of 2019-nCoV. ACE2 presents in stroma and granulosa cells as well as oocytes in immature rat ovaries, the expression of which is enhanced in antral and preovulatory follicles subjected to equine CG treatment (Pereira et al., 2009) . In bovine theca cells and granulosa cells, ACE2 also exists (Barreta et al., 2015; Tonellotto dos Santos et al., 2012) . Notably, ACE2 mRNA transcripts were detected in ovaries from reproductive-age women and postmenopausal women . We analyzed ACE2 data from the GeneCards (https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACE2#protein_expression) database, and found that ACE2 is most abundantly expressed in the ovary. In the meantime, data obtained from Bgee (https://bgee.org/?page=gene&gene_id=ENSG00000130234) showed that the expression level of ACE2 in oocytes is relatively high. Therefore, the ovary and oocyte might be potential targets of 2019-nCoV. ACE2 is the key enzyme in the axis that plays a synergistic role in balancing the levels of Ang II and Ang-(1-7). Ang II induces steroid secretion (Hayashi et al., 2003; Shuttleworth et al., 2002) , facilitates follicle development (Ferreira et al., 2011; Shuttleworth et al., 2002) and oocyte maturation (Giometti et al., 2005; Stefanello et al., 2006; Yoshimura et al., 1992) , contributes to follicular atresia (Kotani et al., 1999; Obermuller et al., 2004; Tanaka et al., 1995) , influences ovulation (Acosta et al., 2000; Ferreira et al., 2007; Guo et al., 2012; Kuji et al., 1996; Kuo et al., 1991; Miyabayashi et al., 2005; Pellicer et al., 1988; Yoshimura et al., 1992; Yoshimura et al., 1993) and maintains corpus luteum progression (Sugino et al., 2005) . Ang-(1-7) promotes the production of estradiol and progesterone (Costa et al., 2003) and enhances ovulation (Muthalif et al., 1998; Tonellotto dos Santos et al., 2012; Viana et al., 2011) and the resumption of meiosis in the oocyte . A recent study showed that the level of Ang-(1-7) is also associated with the maturation of human oocytes (Cavallo et al., 2017) . ACE2 mRNA has been identified in the uterus of human (Vaz-Silva et al., 2009 ) and rat (Brosnihan et al., 2012) . Vaz-Silva et al. (2009) claimed that ACE2 mRNA is more abundant in epithelial cells than in stromal cells, and higher in the secretory phase than in the proliferative phase (Vaz-Silva et al., 2009) . Moreover, we confirmed the presence of ACE2 in uterus and vagina after analyzing the data from the Human Protein Atlas (https://www.proteinatlas.org/ENSG00000130234-ACE2/tissue) and GeneCards. Noteworthy is the report of a high infection rate among sexual partners of 35 2019-nCoV-positive females (Cui et al., 2020) , suggesting the possibility of sexual transmission. However, the confirmation of sexual transmission still needs extensive investigation. Ang II plays a dual role in vascular bed and endometrium regeneration, and initiates menstruation through spiral artery vasoconstriction (Ahmed et al., 1995; Ahmed, 1996a, 1997) . The balance between Ang II and Ang-(1-7) could regulate the regeneration of endometrium (Vaz-Silva et al., 2009 ) and myometrium activity (Deliu et al., 2011; Vaz-Silva et al., 2012) . Moreover, Ang II increases the proliferation of uterus epithelial and stroma cells and enhances endometrial fibrosis, an effect that can be inhibited by Ang-(1-7) (Hering et al., 2010; Shan et al., 2015; Shan et al., 2014) . Notably, the normal function of Ang II in endometrium is necessary for regular menstrual cycles, and alterations in its distribution and the level of the receptors may be related to dysfunctional uterine bleeding associated with hyperplastic endometria (Li and Ahmed, 1996b) . Furthermore, many authors have described in the literature that intense ACE2 and Ang II expression correlates with the metastasis and prognosis of endometrial carcinoma (Delforce et al., 2017; Shibata et al., 2005; Watanabe et al., 2003) , and highlighted that the increased ACE2/Ang-(1-7)/MAS/AT2R pathway activity in endometrial cancer can be an important mechanism to counteract the actions of Ang II/AT1R (AbdAlla et al., 2001; Kostenis et al., 2005) . ACE2 is widely expressed in human placenta (Valdes et al., 2006) . In placental villi, ACE2 is mainly expressed in the syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle of primary and secondary villi. In the maternal stroma, ACE2 is expressed in the invading and intravascular trophoblast and in decidual cells. ACE2 is also found in arterial and venous endothelium and smooth muscle of the umbilical cord (Valdes et al., 2006) . Of note, ACE2 reaches the highest level in early gestation (Pringle et al., 2011) . During early gestation, ACE2 is expressed in the primary and secondary decidual zone, and in luminal and glandular epithelial cells. During late gestation, ACE2 staining is visualized in the labyrinth placenta, and amniotic and yolk sac epithelium (Ghadhanfar et al., 2017; Neves et al., 2008) . Moreover, Ace2 in placenta of rat begins to increase from mid-gestation (Vaswani et al., 2015) . According to the GeneCards, the expression of ACE2 in the placenta is greater than that detected in the lung, suggesting a possibility of viral infection of the placenta. Recently, early-onset 2019-nCoV infection was identified in infants whose nasopharyngeal and anal swabs were positive on Day 2 and 4 of life (Zeng et al., 2020) , and a neonate born to a mother with COVID-19 had elevated IgM antibodies at 2 hours after birth (Dong et al., 2020) . Given that the identification of 2019-nCoV in human airway epithelial cells requires at least 96 hours of culture (National Health Commission of the People's Republic of China, 2020), we speculate that intrauterine infection with 2019-nCoV may appear and the fetuses may be infected during gestation. Additionally, the Human Protein Atlas and GeneCards database showed the presence of ACE2 in female breasts. Wu et al. (2020) claimed that 1 of 3 samples of breast milk was positive for 2019-nCoV in nucleic acid testing (Wu, 2020) , indicating the chance of transmission through breastfeeding. Even if there is no virus in milk, contact transmission during breastfeeding should be taken into account. Given the weaker immune system of newborns, we advise that pregnant patients who are confirmed as positive for 2019-nCoV should carry out artificial feeding instead, or start breastfeeding after a 14-day isolation following recovery and discharge. Concurrently, considering its benefits in decreasing respiratory tract and gastrointestinal tract infections, sudden infant death syndrome and diabetes of the infants (Section on Breastfeeding, 2012), breastfeeding might not be completely forbidden. Nevertheless, Ferrazzi et al. (2020) reported that when breastfed by two postpartum women diagnosed with COVID-19 and wearing no masks, the newborns tested positive (Ferrazzi et al., 2020) . We strongly support that all possible precautions should be taken to avoid spreading the virus to the infant, including washing hands before touching the infant and wearing a face mask during breastfeeding (Baud et al., 2020) . However, these precautions may not be strictly adhered to, hence increasing the risk of infection in the infants. Therefore, mothers who intend to breastfeed are encouraged to use a dedicated breast pump, and after each pumping session, the breast pump should be appropriately disinfected. During pregnancy, Ang II, ACE2 and Ang-(1-7) function mainly through regulating blood pressure and fetus development. Meanwhile, they also interact to maintain normal uterine physiology. Ang II stimulates trophoblast invasion in rat and human cells (Hering et al., 2010) . Ang-(1-7) and ACE2 may act as a local autocrine/paracrine regulator in the early (angiogenesis, apoptosis, and growth) and late (uteroplacental blood flow) events of pregnancy . ACE2 hydrolyzes Ang II into Ang-(1-7), and Ang I into Ang-(1-9), which is quickly converted to Ang-(1-7) and thereby controlling the blood pressure and hydro-salinity balance of pregnant women (Pringle et al., 2011) . The aberrant expression of Ang II, ACE2 and Ang-(1-7) may be involved in hypertension of pregnancy, pre-eclampsia and eclampsia (Anton et al., 2009; Anton et al., 2008; Brosnihan et al., 2004; Merrill et al., 2002; Sykes et al., 2014; Yamaleyeva et al., 2014) . Brosnihan et al. (2004) described that pre-eclamptic women presented with suppressed plasma Ang-(1-7) levels when compared with normal pregnancy subjects (Brosnihan et al., 2004) . High expression of Ang II in the placental villus during pre-eclampsia causes a decreased blood flow and nutrition supply in fetuses (Anton et al., 2009; Anton et al., 2008; Shibata et al., 2006) . Meanwhile, low levels of ACE2 and Ang-(1-7) in placenta are associated with intrauterine growth restriction (Ghadhanfar et al., 2017) . In gestational Ace2 -/mice, plasma Ang-(1-7) decreases and placental Ang II increases, accompanied by abnormal placental functions (including placental hypoxia and uterine artery dysfunction) and ultimately fetal growth retardation (Bharadwaj et al., 2011; Yamaleyeva et al., 2015) . Moreover, Chen et al. (2014) found that the maternal Ang-(1-7)/Ang II ratio is independently associated with gestational hypertension or pre-eclampsia, factors causing preterm birth . Additionally, it has been shown that the up-regulation of ACE2/Ang-(1-7)/Mas prevents premature birth (Lumbers, 2020) . It is noteworthy that premature birth and intrauterine growth restriction may predict the cardiovascular disorders that appear in adulthood (Irving et al., 2000) . Bessa et al. (2019) reported that activation of the ACE2/Ang-(1-7)/Mas axis in hypertensive pregnant rats could attenuate the cardiovascular dysfunction in adult offspring (Bessa et al., 2019) , confirming the engagement of the ACE2 axis in pregnancy. 2019-nCoV infection poses a great threat to pregnant women and fetuses, causing premature birth (20.8%, 25/120), fetal distress (26.7%, 12/45), premature rupture of fetal membranes (13.0%, 10/77) and cesarean section (92.6%, 63/68) Chen et al., 2020b; Ferrazzi et al., 2020; Li et al., 2020a; Liu et al., 2020; Zeng et al., 2020; Zhu et al., 2020) . The considerable cesarean section rate is mainly due to the concern about 2019-nCoV and obstetrical indications (Chen et al., 2020b) . It is worth mentioning that current data are still insufficient and some reports lack concrete details. Therefore, whether it is 2019-nCoV/ACE2 that causes the placental dysfunction remains elusive and needs further evaluation. Moreover, just like SARS-CoV patients, patients infected with 2019-nCoV also demonstrate complicated acute renal impairment, renal dysfunction and renal failure (Chu et al., 2005; Fan et al., 2020; Li et al., 2020b; Li et al., 2020d; Zhang et al., 2020a) . Pacciarini et al. (2008) found that SARS-CoV infects human tubular kidney cells (Pacciarini et al., 2008) . Of note is that ACE2 level in the renal tubules of pregnant mice increases by 117% compared to non-pregnant mice, which may contribute to the maintenance of blood pressure (Brosnihan et al., 2003) . We suppose that pregnant women with COVID-19 may be susceptible to renal injury. 2019-nCoV may infect the ovary, uterus, vagina and placenta through the ubiquitous expression of ACE2. Moreover, 2019-nCoV/ACE2 may disturb the female reproductive functions, resulting in infertility, menstrual disorder and fetal distress. We suggest a following-up and evaluation of fertility after recovery from 2019-nCoV infection, and delaying becoming pregnant, if possible, especially for young female patients. Moreover, we should persistently pay close attention to the situation of pregnant patients as well as fetuses, and take timely measures. What is more, to decrease the incidence of 2019-nCoV infection, special nursing should be conducted for healthy pregnant women, puerperants and newborn infants. The angiotensin II AT2 receptor is an AT1 receptor antagonist Periovulatory changes in the local release of vasoactive peptides, prostaglandin f(2alpha), and steroid hormones from bovine mature follicles in vivo Localization of the angiotensin II and its receptor subtype expression in human endometrium and identification of a novel high-affinity angiotensin II binding site The uterine placental bed Renin-Angiotensin system in normal and preeclamptic pregnancy Activation of local chorionic villi angiotensin II levels but not angiotensin (1-7) in preeclampsia The components of the angiotensin-(1-7) system are differentially expressed during follicular wave in cattle Angiotensin II induces contraction and proliferation of human hepatic stellate cells COVID-19 in pregnant women -Authors' reply. The Lancet Infectious Diseases Stimulation of the ACE2/Ang-(1-7)/Mas axis in hypertensive pregnant rats attenuates cardiovascular dysfunction in adult male offspring Angiotensin-converting enzyme 2 deficiency is associated with impaired gestational weight gain and fetal growth restriction Decidualized pseudopregnant rat uterus shows marked reduction in Ang II and Ang-(1-7) levels Angiotensin-(1-7): a novel vasodilator of the coronary circulation Enhanced expression of Ang-(1-7) during pregnancy Enhanced renal immunocytochemical expression of ANG-(1-7) and ACE2 during pregnancy Effects of angiotensin II and vasopressin on human smooth muscle cells in vitro Angiotensin-(1-7) in human follicular fluid correlates with oocyte maturation Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Clinical Characteristics of Pregnant Women with Covid-19 in Wuhan, China Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study -7) are associated with preterm birth Acute renal impairment in coronavirus-associated severe acute respiratory syndrome ): a novel peptide in the ovary Clinical features and sexual transmission potential of SARS-CoV-2 infected female patients: a descriptive study in Wuhan Expression of renin-angiotensin system (RAS) components in endometrial cancer Intracellular angiotensin II activates rat myometrium Possible Vertical Transmission of SARS-CoV-2 From an Infected Mother to Her Newborn A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9 ACE2 Expression in Kidney and Testis May Cause Kidney and Testis Damage After 2019-nCoV Infection Mode of Delivery and Clinical Findings in COVID-19 Infected Pregnant Women in Northern Italy Angiotensin-(1-7): cardioprotective effect in myocardial ischemia/reperfusion Angiotensin II signaling promotes follicle growth and dominance in cattle The role of angiotensin II in the early stages of bovine ovulation The role of ACE2, angiotensin-(1-7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction Chronic infusion of angiotensin-(1-7) improves insulin resistance and hypertension induced by a high-fructose diet in rats Angiotensin II reverses the inhibitory action produced by theca cells on bovine oocyte nuclear maturation Expression and regulation of Ang-2 in murine ovaries during sexual maturation and development of corpus luteum Intrarenal control of electrolyte excretion by angiotensin II Involvement of angiopoietin-tie system in bovine follicular development and atresia: messenger RNA expression in theca interna and effect on steroid secretion Effects of circulating and local uteroplacental angiotensin II in rat pregnancy Angiotensin II stimulates the proliferation of osteoblast-rich populations of cells from rat calvariae Evidence that angiotensin-(1-7) is an intermediate of gonadotrophin-induced oocyte maturation in the rat preovulatory follicle Clinical features of patients infected with 2019 novel coronavirus in Adult cardiovascular risk factors in premature babies Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects Stimulation of renal sodium reabsorption by angiotensin II G-Protein–Coupled Receptor Mas Is a Physiological Antagonist of the Angiotensin II Type 1 Receptor Biological roles of angiotensin II via its type 2 receptor during rat follicle atresia A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury Involvement of angiotensin II in the process of gonadotropin-induced ovulation in rabbits Direct effect of angiotensin II on in-vitro perfused rabbit ovary Maternal and neonatal outcomes of pregnant women with COVID-19 pneumonia: a case-control study Clinical characteristics of 25 death cases infected with COVID-19 pneumonia: a retrospective review of medical records in a single medical center Dual role of angiotensin II in the human endometrium Expression of angiotensin II and its receptor subtypes in endometrial hyperplasia: a possible role in dysfunctional menstruation Compartmentalization and cyclic variation of immunoreactivity of renin and angiotensin converting enzyme in human endometrium throughout the menstrual cycle The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Caution on Kidney Dysfunctions of 2019-nCoV Patients Angiotensin-(1-7) suppresses oxidative stress and improves glucose uptake via Mas receptor in adipocytes Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Chapter 10 -The Physiological Roles of the Renin-Angiotensin Aldosterone System and Vasopressin in Human Pregnancy Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study Angiotensin-(1-7) in normal and preeclamptic pregnancy Changes of mRNA expression of vascular endothelial growth factor, angiopoietins and their receptors during the periovulatory period in eCG/hCG-treated immature female rats Signal transduction mechanisms involved in angiotensin-(1-7)-stimulated arachidonic acid release and prostanoid synthesis in rabbit aortic smooth muscle cells National Health Commission of the People's Republic of China. The notice of launching guideline on diagnosis and treatment of the novel coronavirus pneumonia ACE2 and ANG-(1-7) in the rat uterus during early and late gestation Immunohistochemical and mRNA localization of the angiotensin II receptor subtype 2 (AT2) in follicular granulosa cells of the rat ovary Synergistic effect of angiotensin-(1-7) on bradykinin arteriolar dilation in vivo Persistent replication of severe acute respiratory syndrome coronavirus in human tubular kidney cells selects for adaptive mutations in the membrane protein Blockage of ovulation by an angiotensin antagonist Gonadotropin stimulation increases the expression of angiotensin-(1--7) and MAS receptor in the rat ovary The expression and localization of the human placental prorenin/renin-angiotensin system throughout pregnancy: roles in trophoblast invasion and angiogenesis? Angiotensin II receptor-mediated proliferation of cultured human fetal mesangial cells Angiotensin-(1-7), its receptor Mas, and the angiotensin-converting enzyme type 2 are expressed in the human ovary Angiotensin-(1-7) is a modulator of the human renin-angiotensin system Expression of an angiotensin-(1-7)-producing fusion protein produces cardioprotective effects in rats Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas Section on Breastfeeding. Breastfeeding and the use of human milk Effect of angiotensin-(1-7) and angiotensin II on the proliferation and activation of human endometrial stromal cells in vitro Angiotensin-(1-7) and angiotensin induce the transdifferentiation of human endometrial epithelial cells in vitro Angiotensin II decreases system A amino acid transporter activity in human placental villous fragments through AT1 receptor activation Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma In vitro development of pig preantral follicles cultured in a serum-free medium and the effect of angiotensin II Effect of angiotensin II with follicle cells and insulin-like growth factor-I or insulin on bovine oocyte maturation and embryo development Angiogenesis in the human corpus luteum: changes in expression of angiopoietins in the corpus luteum throughout the menstrual cycle and in early pregnancy Fetal sex and the circulating renin-angiotensin system during early gestation in women who later develop preeclampsia or gestational hypertension Characterization of angiotensin II receptor type 2 during differentiation and apoptosis of rat ovarian cultured granulosa cells A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase Molecular characterization and regulation of the angiotensin-converting enzyme type 2/angiotensin-(1-7)/MAS receptor axis during the ovulation process in cattle Distribution of angiotensin-(1-7) and ACE2 in human placentas of normal and pathological pregnancies The rat placental renin-angiotensin system -a gestational gene expression study The vasoactive peptide angiotensin-(1-7), its receptor Mas and the angiotensin-converting enzyme type 2 are expressed in the human endometrium Tissue specific localization of angiotensin-(1-7) and its receptor Mas in the uterus of ovariectomized rats Angiotensin-(1-7) induces ovulation and steroidogenesis in perfused rabbit ovaries Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Increasing Host Cellular Receptor-Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection Adipocyte-derived leucine aminopeptidase suppresses angiogenesis in human endometrial carcinoma via renin-angiotensin system World Health Organization. Coronavirus disease (COVID-2019) situation reports Viral Shedding of COVID-19 in Pregnant Women Intraovarian actions of anti-angiogenic agents disrupt periovulatory events during the menstrual cycle in monkeys Local delivery of angiopoietin-2 into the preovulatory follicle terminates the menstrual cycle in rhesus monkeys Hemodynamic responses to angiotensin-(1-7) in women in their third trimester of pregnancy Uterine artery dysfunction in pregnant ACE2 knockout mice is associated with placental hypoxia and reduced umbilical blood flow velocity Angiotensin II directly induces follicle rupture and oocyte maturation in the rabbit Locally produced angiotensin II induces ovulation by stimulating prostaglandin production in in vitro perfused rabbit ovaries Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China Clinical characteristics of 82 death cases with COVID-19 Liver injury in COVID-19: management and challenges COVID-19 and the cardiovascular system A pneumonia outbreak associated with a new coronavirus of probable bat origin Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia This work was supported by National Natural Science Foundation of China (No.31801172). None declared.