Regulation of Vascular Injury and Repair by P21-Activated Kinase 1 and P21-Activated Kinase 2: Therapeutic Potential and Challenges

Abstract

The PAK (p21-activated kinases) family is a class of intracellular signal transduction protein kinases that regulate various cellular functions, mainly through their interactions with small GTP enzymes. PAK1 and PAK2 in the PAK kinase family are key signal transduction molecules that play important roles in various biological processes, including morphological changes, migration, proliferation, and apoptosis, and are involved in the progression of many diseases. Abnormal expression or dysregulation of PAK1 and PAK2 may be associated with several diseases, including cancer, neurological diseases, etc. The current research mainly focuses on studying the role of PAK and PAK inhibitors in the regulation of cancer progression, but relatively few reports are available that explore their potential role in cardiovascular diseases. Vascular injury and repair are complex processes involved in many cardiovascular conditions, including atherosclerosis, restenosis, and hypertension. Emerging research suggests that PAK1 and PAK2 have pivotal roles in vascular endothelial cell functions, including migration, proliferation, and angiogenesis. These kinases also modulate vascular smooth muscle relaxation, vascular permeability, and structural alterations, which are critical in the development of atherosclerosis and vascular inflammation. By targeting these activities, PAK proteins are essential for both normal vascular physiology and the pathogenesis of vascular diseases, highlighting their potential as therapeutic targets for vascular health. This review focuses on recent studies that offer experimental insights into the mechanisms by which PAK1 and PAK2 regulate the biological processes of vascular injury and repair and the therapeutic potential of the current existing PAK inhibitors in vascular-related diseases. The limitations of treatment with some PAK inhibitors and the ways that future development can overcome these challenges are also discussed.

Keywords: P21-activated kinase; angiogenesis; inflammation; signaling pathway; vascular permeability; vascular remodeling.

Figure 1

The schematic representation of the domain architecture of PAK1 and PAK2 in mammals. The Nck domain is shown in dark blue. The light blue area represents the self-inhibition dimer interface, which overlaps with both the p21-binding domain and the inhibition region shown in red. Another SH3-binding domain, PIX, is depicted in pink, while the yellow section represents the kinase domain. Finally, the activated dimer interface shown in green is situated in the kinase domain.

Figure 2

The activation process of PAK. PAK contains a PBD domain that can bind the active forms of Cdc42 and Rac 1 in the small GTPase family. When Cdc42 or Rac1 are in the active state, they bind to the PBD domain of PAK, causing a conformational change in PAK.

Figure 3

Roles of PAK1 and PAK2 in vascular cells. PAK1 primarily influences cytoskeletal dynamics and cell migration to regulate vascular stability and repair by targeting various cell types across the three tunics of blood vessels. PAK2, on the other hand, predominantly impacts angiogenesis, immune cell proliferation, and cell cycle progression. Collectively, both PAK1 and PAK2 have the capacity to modulate cell adhesion, vascular wall remodeling, and the stability of tissue connections.

Figure 4

Roles of PAK1 and PAK2 in vascular remodeling. PAK1 exerts its influence on cell proliferation by activating Rac1 through the MAPK signaling pathway, while PAK2 mitigates ROS-induced activation and endothelial apoptosis by inhibiting BAD and Caspase-3. Collectively, PAK1 and PAK2 target VSMCs, impacting their migration and thereby playing a significant role in vascular remodeling.

Figure 5

Role of PAK1 and PAK2 in angiogenesis. PAK1 and PAK2 can target MMPs and the cell cycle, thereby influencing the extracellular matrix and the proliferation of endothelial cells. Additionally, PAK1 can target Rac1, which affects the migration of VSMCs. PAK2, on the other hand, influences the formation of endothelial cells through the MAPK/Erk 5 pathway, as well as through the activation of VEGF and paxillin to regulate the cytoskeleton.

Figure 6

Roles of PAK1 and PAK2 in the regulation of vascular integrity and permeability. PAK1 and PAK2 collaboratively modulate vascular integrity and endothelial function by targeting VE-cadherin, which affects the stability of intercellular junctions. PAK1 exerts its individual influence on platelet activation and apoptosis through the Notch signaling pathway and directly impacts vascular permeability via VEGF. Meanwhile, PAK2 regulates the formation of cell pseudopodia and adhesion sites through interactions with AF6, LIMK, and β-Pix, thereby affecting endothelial permeability.

Figure 7

Roles of PAK1 and PAK2 in vascular inflammatory response. PAK1 and PAK2 can affect ROS and the activation and migration of immune cells through the NF-κB pathway, thus affecting the vascular inflammatory response; in addition, PAK2 can also act on prostaglandins alone to affect the vascular inflammatory response.