*3.3.2 Ca2+ exchange through ER*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

(**Figure 2**). This signaling pathway can be terminated by removing cGMP through converting cGMP to GMP by various phosphodiesterases (PDE) [35]. There are many types of PDE in the human body, and they play critical roles in regulating cardiovascular function, adrenal steroidogenesis, and phototransduction [35]. Interestingly, protein kinase A (PKA, cAMP-dependent protein kinase) and PKG share very similar nucleotide binding domains. Many studies have shown that cGMP can activate PKA downstream pathways and cAMP can also cross-activate PKG [36]. This cross regulation between cGMP and cAMP pathways sometimes

*Biosynthesis of NO by eNOS and the biological effects of NO in the vascular system.*

Due to NO's vasodilation effect, NO releasing drugs such as organic nitrate, and nitro- and nitroso compounds have been used for treating angina pectoris, congestive heart failure damage from ischemia–reperfusion, and pulmonary hypertension [37, 38]. Potent drugs also include chemicals that target members involved in NO-cGMP pathway. For example, Sildenafil, known as Viagra, is a PDE5 inhibitor. It prohibits cGMP from being hydrolyzed by PDE5 and extends the activation time of vasodilation to widen the blood vessel and increases blood flow into the penis to

To fully understand how NO causes vasodilation, it is necessary to perceive the relationship between NO-cGMP pathway and [Ca2+]i. At rest, extracellular Ca2+ concentration is high (1–2 mM), while the cytosolic Ca2+ is over 1000 times lower (>1 μM) [40, 41]. In the endoplasmic reticulum (ER, or SR in cardiac muscles), Ca2+ concentration is also high (about 400 μM) [40]. NO modulates [Ca2+]i by control-

Voltage-gated Ca2+ channels regulate [Ca2+]i through sensing electrical signals to allow Ca2+ entering the cell. High voltage-activated L-type channels are broadly found in the cardiovascular system. L-type Ca2+ channel inhibitors, such as dihydropyridines, phenylalkylamines, and benzothiazepines, are a major class of drugs for treating CVDs [42]. The opening probability of L-type Ca2+ channel can be

complicates NO signaling, which will be shown later.

**3.3 NO-induced muscle relaxation through Ca2+ signaling**

ling Ca2+ exchange mechanisms on both cell and SR membranes.

*3.3.1 Ca2+ exchange through plasma membrane*

treat erectile dysfunction [39].

**Figure 2.**

**8**

Ca2+ pump ATPase also resides on the ER responsible for the uptake of cytosolic Ca2+ into the ER. NO pathway regulates ER Ca2+ pumping through phosphorylation of phospholamban by PKG [51]. Mainly identified in cardiac tissues, phospholamban is an inhibitor of SR Ca2+ pump. Phospholamban is normally phosphorylated by PKA, which diminishes its inhibitory effect to Ca2+ pump [52]. Interestingly, in neonatal cardiomyocytes and vascular SMCs, NO pathway also demonstrated relaxation effect through differentially phosphorylating phospholamban [53, 54].

Inosital 1,4,5-trisphosphate (IP3) is a critical messenger molecule that can induce Ca2+ release from the ER reservoir. IP3 receptor resides on the ER and works as a chemical-activated Ca2+ channel. NO-cGMP pathway can reduce IP3 generation [55], and PKG can phosphorylate and inactivate IP3 receptor in vascular SMCs to inhibit ER Ca2+ release [35, 56].
