Page 28 - Haematologica Vol. 109 - July 2024

SPOTLIGHT REVIEW ARTICLE - Coagulation factors and endothelial functionality C. Olgasi et al.
Thus, studying the crossroads between hemostasis and angiogenesis would promote better understanding of vas- cular dynamics. This review aims to explore this intricate interplay, deciphering the dual facets of some CF, not merely as hemostatic agents, but also as regulators of EC functionality.
The role of several coagulation factors on endothelial cell functionality
Thrombin
Thrombin, a multifaceted enzyme pivotal in hemostasis, plays a critical role in forming clots by cleaving fibrinogen into fibrin, generating the structural backbone of clots that entrap platelets and blood cells to arrest blood flow from injured vessels. It amplifies the coagulation cascade by activating the platelets, further helping clot formation at injury sites. Its influence extends beyond coagulation, triggering inflammation and specific signaling pathways through G protein-coupled receptors (GPCR), particularly protease-activated receptor 1 (PAR1), across various cell types.1
Interestingly, thrombin has been demonstrated to impact on EC in several different ways, including increasing their permeability. Indeed, thrombin disrupts the endothelial barrier, influencing the organization and disassembly of cell-cell adhesion proteins.4 By binding to GPCR, thrombin decreases cyclic adenosine 3′,5′-monophosphate (cAMP) and increases Ca2+ levels through specific secondary medi- ators, resulting in endothelial cytoskeleton rearrangement and regulation of Ras homologous (Rho) family GTPases, ultimately leading to increased permeability.5 Recent phos- pho-proteomic analyses of thrombin-stimulated EC un- veiled a novel non-canonical thrombin-mediated pathway through p38 mitogen-activated protein (MAP) kinase, pro- moting EC barrier disruption.6 Furthermore, corroborating this hypothesis, some studies indicate that thrombin induc- es capillary tube regression akin to other pro-inflammatory agents and is responsible for endothelial dysfunction while the inhibition of its activity partially restores physiological EC homeostasis.7
Consequently, extensive research has been carried out to probe into the angiogenic role of thrombin and its impact on tumor development. Notably, thrombin elevates the ex- pression of various angiogenic factors like angiopoietin-2, growth-regulated oncogene (GRO-α) and VEGF through c-FOS transcriptional regulation in in vitro EC culture.8 It has also been described as increasing cancer invasion enhancing the expression of matrix metalloproteinase-9 and integrin beta1 (b1) on the cell surface9 and promoting vasculogenic mimicry, a process which transforms tumor cells into EC, through PAR1 and nuclear factor kappaB
(NF-κB) signaling.10 Its angiogenic potential is also evident in rat brains, where it enhances new vessel formation af- ter intracranial hemorrhage, and its inhibition preserves blood-brain barrier integrity.11 In agreement with this, a role in murine embryonic vascular development has been shown for PAR1, and its inhibition results in reduced angio- genesis and attenuated permeability in in vivo models.12,13 Interestingly, thrombin has been observed to control EC functions not only through PAR, but also directly binding integrin alpha-v-beta3 (αvb3) and promoting EC attach- ment, migration and survival.14 The binding of thrombin with integrins should not be surprising, considering the pivotal role of these receptors in finely regulating EC functions. However, the role of thrombin on the in vitro formation of vascular tubule networks remains a topic of debate, con- tingent upon the quantity of thrombin employed for EC stimulation: high concentrations enhance EC permeability through great PAR1 activation, while lower doses exhibit a protective effect, mainly cleaving PAR3.15 Additionally, thrombin has been associated with both venoconstriction and arterial vasodilation, highlighting the complexity of its role in endothelium biology.16
Current data suggest that thrombin induces unique but conflicting responses within the human vasculature (Table 1), emphasizing the need for new studies to confirm its action on EC.
Factor VIII and von Willebrand factor
Factor VIII (FVIII) and its partner, von Willebrand factor (vWF), engage in a tightly co-ordinated interplay with- in the coagulation cascade, forming a complex that is pivotal for hemostasis. vWF acts as a carrier protein for FVIII, safeguarding it from premature degradation in the bloodstream. Upon vascular injury, vWF adheres to exposed collagen at the injury site, facilitating platelet adhesion and aggregation. This localization of vWF-bound FVIII primes the coagulation process, enabling FVIII to interact with activated platelets and initiate the coagulation cascade, increasing the catalytic activity of factor IX (FIX) and, thus, activating factor X (FX).17
Given the primary production of FVIII by EC,18 recent stud- ies have been investigating the link between FVIII and EC functionality. Specifically, FVIII has been shown to induce transcriptional and functional changes in EC leading to a decrease in in vitro adherence and increased permeabil- ity, with paxillin as main mediator of these changes.19 An altered and uncontrolled joint vascular remodeling has also been shown in FVIII-deficient mice after induction of hemarthrosis, suggesting a non-physiological angiogenic mechanism which could be a contributing cause of pro- longed and repetitive bleedings.20 Indeed, hemophilia A (HA) patients show reduced flow-mediated dilation (FMD) and hyperemic velocity time integral (VTI) compared to healthy controls,21 pointing to alterations of both mac- rovascular and microvascular endothelial functions for
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