Federica Campolo ^1* Arun Samidurai ²

• ¹ Sapienza University of Rome, Rome, Italy
• ² Virginia Commonwealth University, Richmond, Virginia, United States

critical second messengers involved in numerous cellular functions, including metabolism, 10 endocrine system and cancer (1). The level, compartmentalization and amplitude of cAMP/cGMP 11 responses are finely regulated by phosphodiesterases (PDEs) that are responsible for the hydrolysis 12 of cyclic nucleotides in a spatio-temporal manner (2). PDEs are classified into eleven families 13 (PDE1-PDE11) based on their specificity for cyclic nucleotides, structural homology and 14 mechanism of regulation (1). PDE family of enzymes are encoded by more than 20 genes and 15 undergo extensive splicing processes, giving rise to more than 100 different isoforms that are 16 widely expressed in mammalian tissues (2,3). PDEs govern the cellular levels of cAMP and cGMP 17 and execute their function through their downstream protein kinase A (PKA) and protein kinase G 18 (PKG) respectively. While PDE inhibitors (PDEi) have been successfully used for the treatment 19 of many disorders including erectile dysfunction (ED), pulmonary arterial hypertension (PAH) and 20 lower urinary tract disease (LUTD), new evidences suggested a possible use of PDEi for the 21 treatment of cardiovascular diseases (CVD), cancer and metabolic disorders (4-8). Given the 22 pivotal role of cyclic nucleotides in regulating many aspects of endocrine system physiology, 23 pharmacological enhancement of cAMP/cGMP through PDEi, has been also considered as a 24 valuable strategy for the treatment of endocrine disorders. Both cAMP and cGMP actively 25 participate in the regulation of the endocrine system modulating hormone release in several 26 endocrine tissues. The first evidence of an involvement of cGMP in the regulation of hormone 27 release comes from the pioneering research of McKee et al., that reconstructed the intricate 28 signaling governing hormonal release at renal level that involve nitric oxide and cGMP (9). In the 29 hypothalamus, cGMP can stimulate the release of gonadotropin-releasing hormone, which is 30 essential for reproductive function (10). cGMP signaling interacts with other signaling cascades, including cAMP and calcium signaling, to fine-tune endocrine responses. This cross-talk allows 32 for complex integration of various signals and contributes to the precise control of hormone action 33 (11). Like and more than its cognate, cAMP regulates the production and release of various 34 hormones. In the adrenal cortex, cAMP stimulates the synthesis and secretion of cortisol in 35 response to ACTH (12). Similarly, in the thyroid gland, cAMP mediates the effects of TSH on 36 thyroid hormone production (13). For instance, in the pituitary gland, cAMP can stimulate cell 37 proliferation and hormone production ( 14). These observations suggest that different cellular and 38 molecular alterations of cAMP-signaling pathway have been identified in endocrine-related 39 diseases. Changes in cAMP signaling pathways have also been linked to tumorigenesis at different 40 proliferation. PDEs also play an important role in the regulation of renin-angiotensin-aldosterone 75 system (RAAS), a key endocrine mechanism that controls blood pressure and fluid balance in the 76 body (26,27) . In this special issue, review article by Gambaryan et al ., summarizes the role of 77 PDE in the renin-angiotensin-aldosterone system (RAAS). Renin secreted by Juxtaglomerular 78 (JG) cells and aldosterone produced by Zona glomerulosa (ZG) cells are influenced by the cellular 79 levels of cAMP and cGMP and hence PDEs (29). Regulation of RAAS by PDEs is highly complex 80 and involves intrigue cross-talk between cAMP and cGMP signaling orchestrated by PDEs. The 81 secretion of renin is predominantly mediated by cAMP/PKA pathway involving exchange proteins 82 activated by cAMP (EPAC) (28). However, the role of cGMP in the activation of renin remains 83 unclear and studies suggest that cGMP could both activate as well as inhibit renin. Several 84 members of PDE family are involved in RAAS signaling including PDE1, PDE2, PDE3 and PDE4 85 and PDE9, which are expressed in JG cells. Similarly, PDE2, PDE3, PDE8 and PDE11 are present 86 in ZG cells and its inhibition was shown to influence the level of aldosterone (29). PDEi, especially 87 cilostazol (PDE3i), apremilastis (PDE4i) and sildenafil (PDE5i), are proven to be safe with 88 minimal side effects. Therefore, repurposing PDE inhibitors for other diseases such as cancer, 89Leydig cell tumors and hypertension may be a smart strategy. This special issue highlights the 90 diverse role of PDEs in various diseases pertaining to endocrine system associated to cancer and 91CVDs. Moreover, cutting-edge technologies using single-cell spatial transcriptomics may shed 92 new light on the role of PDEs in the regulation of compartmentalized cAMP/cGMP signaling.