*4.3. Other Actions of APN Related to the Cardiovascular System*

APN activation has been reported in diabetic nephropathy, renal damage, connective vascular disease, and cerebral ischemia [69]. In mice, APN is also essential for inflammatory trafficking after coronary artery occlusion and for sustaining the reparative response [70]. Hence, APN blockade of APN is a therapeutic approach to these vascular abnormalities.

Stimulation of AT4 receptors by APN-generated AngIV exerts proangiogenic action. Thus, APN is augmented in pathologic angiogenesis, especially in tumor vasculature [71], and APN blockade reduces angiogenesis in vivo [72]. In APN-null mice, angiogenesis alterations are manifested in pathological situations but not under physiological conditions [73]. According to these observations, APN activity promotes angiogenesis in various conditions and its blockade prevents new blood vessel growth. Indeed, molecular imaging of APN has been used to detect and monitor multiple types of cancer and the surface of vasculature undergoing angiogenesis in cardiac regeneration [74]. Hence, APN is a potential biomarker of angiogenesis and therapeutic tool.

#### **5. Therapeutic Strategies to Treat Arterial Hypertension with Aminopeptidases**

The vast majority of studies on the control of BP and treatment of hypertension have addressed the blockade of AngII or its receptors, and there has been less research on the regulation of other angiotensin peptides. Thus, blockade of the brain RAS has been found to simultaneously decrease sympathetic tone, vasopressin release, and baroreflex activity, thereby reducing cardiac output and peripheral resistance [75].

An action on central or peripheral APs represents a new approach to the treatment of hypertension. Thus, new antihypertensive treatments have been developed based on potent orally-active inhibitors of APA or activators of aspartyl-aminopeptidase (DNPEP), since brain aspartyl aminopeptidase exerts BP-lowering effects by transforming AngI into angiotensin 2-10. Currently, the search for new antihypertensive compounds that affect the RAS multi-enzyme cascade is an important line of research.
